Basic Pharmacokinetics - Chapter 10: Dosage

CHAPTER 10

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Author: Michael Makoid Reviewer: Phillip Vuchetich

OBJECTIVES 1.

Given population average patient data, the student will devise (V) dosage regimens which will maintain plasma concentrations of drug within the therapeutic range.

2.

Given specific patient information, the patient will justify (VI) dosage regimen recommendations.

3.

Given patient information regarding organ function, the student will devise (V) and justify (VI) dosage regimen recommendations for the compromised patient.

4.

The student will write (V) a professional consult using the above calculations

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10-1

Dosage Regimen (Healthy, Aged, and Diseased Patients)

10.1 Therapeutic Drug Monitoring 10.1.1

THERAPEUTIC RANGE The pharmacokinetics of a drug determine the blood concentration achieved from a prescribed dosing regimen. During multiple drug dosing, the blood concentration will reflect the drug concentration at the receptor site; and it is the receptor site concentration that determines the intensity of the drug’s effect. Therefore, in order to predict a patient’s response to a drug regimen, both the pharmacokinetics and pharmacological response characteristics of the drug must be understood. There exists a fundamental relationship between drug pharmacokinetics and pharmacologic response. The relationship between response and ln-concentration is sigmoidal. A threshold concentration of drug must be attained befor any response is ellicited at all. Therapy is accheived when the desired effect is attained because the required concentration has been reached. That concentration would set the lower limit of utility of the drug, and is called Effective Concentration (MEC). Most drugs are not “clean”, that is exhibit only the desired therapeutic response. They also exhibit undesired side effects, sometimes called toxic effects at a higher, hopefully a lot higher, concentration. At some concentration, these toxic side effects become become intollerable. That concentration, or one below it, would set the upper limit of utility for the drug and is called the Maximum Therapeutic Concentration or Minimum Toxic Concentration (MTC). Patient studies have generated upper (MTC) and lower (MEC) plasma concentration ranges that are deemed safe and effective in treating specific disease states. These concentrations are known as the “therapeutic range” for the drug (see Table 10-1).When a drug is administered at a fixed dosage to numerous subjects, the blood concentrations achieved vary greatly due to biological variation. However it is possible to have a reasomable Clinically, digoxin concentrations below 0.8 ng ⁄ ml will elicit a subtherapeutic effect. Alternatively, when the digoxin concentration exceeds 2.0 ng ⁄ ml side effects occur (nausea and vomiting, abdominal pain, visual disturbances). Drugs like digoxin possess a narrow therapeutic index because the concentrations that

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10-2

Dosage Regimen (Healthy, Aged, and Diseased Patients)

may produce toxic effects are close to those required for therapeutic effects. The importance of considering both pharmacokinetics and pharmacodynamics is clear. TABLE 10-1. Average

therapeutic drug concentration

DRUG

RANGE

digoxin

0.8-2.0 ng ⁄ ml

gentamicin

2-10 µg ⁄ ml l

lidocaine

1-4 µg ⁄ ml

lithium

0.4-1.4 mEq ⁄ L

phenytoin

10-20 µg ⁄ ml

phenobarbitol

10-30 µg ⁄ ml

procainamide

4-8 µg ⁄ ml

quinidine

3-6 µg ⁄ ml

theophylline

10-20 µg ⁄ ml

Note that drug concentrations may be expressed by a variety of units. Pharmacokinetic factors that cause variability in plasma drug concentration are: • • • • •

Drug-drug interaction patient disease state physiological states such as age, weight, sex drug absorption variation differences in the ability of a patient to metabolize and eliminate the drug

If we were to give an identical dose of drug to a large group of patients and then measure the highest plasma drug concentration we would see that due to individual variability, the resulting plasma drug concentrations differ. This variability can be attributed to factors influencing drug absorption, distribution, metabolism, and excretion. Therefore, drug dosage regimens must take into account any disease altering state or physiological difference in the individual. Therapeutic drug monitoring optimizes a patient’s drug therapy by determining plasma drug concentrations to ensure the rapid and safe drug level in the therapeutic range.

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Dosage Regimen (Healthy, Aged, and Diseased Patients)

Two components make up the process of therapeutic drug monitoring:

• Assays for determination of the drug concentration in plasma • Interpretation and application of the resulting concentration data to develop a safe and effective drug regimen.

The major potential advantages of therapeutic drug monitoring are the maximization of therapeutic drug benefits and the minimization of toxic drug effects. The formulation of drug therapy regimens by therapeutic drug monitoring involves a process for reaching dosage decisions.

10.1.2

THERAPEUTIC MONITORING: WHY DO WE CARE? The usefulness of a drug’s concentration vs. time profile i based on the observation that for many drugs there is a relationship between plasma concentration and therapeutic response. There is a drug concentration below which the drug is ineffective, the Minimum Effective Concentration (MEC), and above which the drug has untoward effects, the Minimum Toxic Concentration (MTC). That defines the range in which we must attempt to keep the drug concentration (Therapeutic Range). The data in Table 10-1 are population averages. Most people respond to drug concentrations in these ranges. There is always the possibility that the range will be different in an individual patient. For every pharmacokinetic parameter that we measure, there is a population average and a range. This is normal and is called biological variation. People are different. In addition to biological variation there is always error in the laboratory assays that we use to measure the parameters and error in the time we take the sample. Even with these errors, in many cases, he therapy is better when we attempt to monitor the patient’s plasma concentration to optimize therapy than if we don’t. This is called therapeutic monitoring. If done properly, the plasma concentrations are rapidly attained and maintained within the therapeutic range throughout the course of therapy. This is not to say all drugs should be monitored. Some drugs have a such a wide therapeutic range or little to no toxic effects that the concentrations matter very little. Therapeutic monitoring is useful when: • • • •

a correlation exists between response and concentration the drug has a narrow therapeutic range the pharmacological response is not easily assessed there is a wide inter-subject range in plasma concentrations for a given dose

In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic monitoring of key drugs can be economically beneficial to an institution. A recent study (DeStache 1990) showed a significant difference with regard to days in the

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10-4

Dosage Regimen (Healthy, Aged, and Diseased Patients)

hospital between the patients on gentamicin who were monitored (and their dosage regulated as a consequence) vs. those who were not. With DRGs the hospital was reimbursed a flat fee irrespective of the number of days the patient stayed in the hospital. If the number of days cost less than what the DRG paid, the hospital makes money. If the days cost more than the hospital loses money. This study showed that if all patients in the hospital who were on gentamicin were monitored, the hospital would save $4,000,000. That’s right FOUR MILLION per year. I would say that would pay my salary, with a little left over, and that is only one drug! The process of therapeutic monitoring takes effort.

• • • • •

First the MD must order the blood assays. Second, someone (nurse, med tech, you) must take the blood. Someone (lab tech, you) must assay the drug concentration in the blood. You must interpret the data You must communicate your interpretation and your recommendations for dosage regimen change to the MD. This will allow for informed dosage decisions.

• You must follow through to ensure proper changes have been made. • You must continue the process throughout therapy. Therapeutic monitoring, in many cases, will be part of your practice. It can be very rewarding

Thus, if we have deterimined the therapeutic range, we could use pharmacokinetics to determine the optimum dosage regemin to maintain the patient’s plasma concentration within that range.

10.1.3

STEADY STATE It is rare that a drug is given only once. Most therapies consist of multiple doses of several days duration, if not several years. It is necessary, therefore, to be able to asess plasma concenterations, both the peak which much be at or below the MTC and the trough which must be at or above the MEC for the drug to be effective under these conditions. Thus when we dose a patient, the concentration profile must be within the Therapeutic Range during the entire time that the patient is taking the drug. We can calculate the plasma concentrations in the followin manner. In the simplest model, suppose we give a drug by IV Bolus (because the math is simpler). The equation which would result be Cp = Cp 0 ⋅ e

I.V. Bolus Multiple Dose

( –kt )

D ( – kt) =  ---- ⋅ e V 

(EQ 10-1)

The peak would be

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10-5

Dosage Regimen (Healthy, Aged, and Diseased Patients)

(EQ 10-2)

1 D Cp max = ---V

If we allowed the drug to be eliminated for

τ

hours, the trough would be:

1 D ( –( k ⋅ τ ) ) Cp min = ---- ⋅ e V

(EQ 10-3)

Upon giving a second dose, prior to the complete removal by the body of the first dose the Cp max 2 would be the second dose plus what was left from the first dose: 2 D D ( – ( k ⋅ τ ) ) Cp max = ---- +  ---- ⋅ e  V V

and the

Cp min

2

would be

Cp max

2

times

e

( –(k ⋅ τ ))

(EQ 10-4)

, thus:

2 ( –( k ⋅ τ ) )  D ( –( 2k ⋅ τ ) ) ---- ⋅ e + ---- ⋅ e : Cp min = D  

V

After n doses, the

Cp max

n

(EQ 10-5)

V

would be:

n (–( k ⋅ τ) ) ( – ( ( n – 1 )k ⋅ τ ) ) Cp max = D ---- + D ---- ⋅ e +…+D ---- ⋅ e V V V

while the

Cp min

n

(EQ 10-6)

would be:

n (–( k ⋅ τ) )  D ( – ( 2k ⋅ τ ) ) ( – ( nk ⋅ τ ) ) Cp min = D ---- ⋅ e + ---- ⋅ e +…+D ---- ⋅ e V  V V

(EQ 10-7)

Subtracting equation 10-7 from equation 10-6 to eliminate the series yields: n – ( nk ⋅ τ ) n D D ( – ( nk ⋅ τ )) D --- ⋅ ( 1 – e ) Cp max – Cp min = ---- –  ---- ⋅ e  = -V V V

Cp min

n

is also

n

Cp max ⋅ e n

–( k ⋅ τ )

n

(EQ 10-8)

which means that n

n

Cp max – Cp min = Cp max – Cp max ⋅ e

–( k ⋅ τ )

n

= Cp max ( 1 – e

Equating equation 10-8 and equation 10-9 and solving for

–( k ⋅ τ )

Cp max

) n

(EQ 10-9)

yields:

–( nk ⋅ τ )

n –e Cp max = D ---- ⋅ 1---------------------------V 1 – e–(k ⋅ τ )

At large n, e – ( nk ⋅ τ ) ⇒ 0 and thus the steady state maximum, Basic Pharmacokinetics

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(EQ 10-10)

Cp max

ss

, is: 10-6

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Cp max

and the steady state minimum,

ss

1 = D ---- ⋅ ------------------------V 1 – e–( k ⋅ τ )

Cp min

Cp min

ss

ss

(EQ 10-11)

, is : –( k ⋅ τ )

D e = ---- ⋅ ------------------------V 1 – e –( k ⋅ τ )

(EQ 10-12)

In order to make a general equation set from equation 10-11 and equation 10-12, let N be the number of half lives in a dosing interval, k = ( ln ( 2 ) ) ⁄ t 1 ⁄ 2

. Substituting into the function

e

–(k ⋅ τ )

, yields

e

τ N = --------t1 ⁄ 2 –( k ⋅ τ )

, and

N = 1 ---  2

and

thus equation 10-11 becomes: Cp max

ss

1 = D ---- ⋅ -------------------V 1 N 1 –  ---  2

(EQ 10-13)

and equation 10-12 becomes : N

Cp min

ss

 1---  2 D = ---- ⋅ --------------------V 1 N 1 –  ---  2

(EQ 10-14)

The average drug concentration under these conditions would be equivalant to the steady state concentration attained by an infusion of the same rate, i.e. if we were to give a multiple dose at 200 mg every four hours (q4h) or 400 mg every eight hours (q8h), the average that would be attained would be equivelaent to the steady state plasma concentration attained by giving an infusion at 50 mg/hr, (Q = 50 mg/ hr), and thus, in the infusion, the k ⋅ τ = 0.693 ⋅ N

ss

Q = ---------k⋅V

and in multiple dosing

D Q = ---τ

, and

so: Cp

Oral Multiple Dosing (Approximation)

Cp

ss avg

D D 1.443 ⋅ D = ------------------- = ------------------------------ = ---------------------V ⋅ K ⋅ τ V ⋅ 0.693 ⋅ N N⋅V

(EQ 10-15)

Similar equations, although more complex, can be derived for multiple dose oral products. However, if we were agreed to live with some error these equations, with some modifications could be used to approximate multiple dose oral products. The error on both calculated Cp maxss and Cp minss would be in the direction of safety, i.e. the calculated Cp maxss would be higher and the calculated Cp minss would be lower that their respective multiple dose oral calculations. Thus, if the simpler

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Dosage Regimen (Healthy, Aged, and Diseased Patients)

equations place the Cp max ss and C minss within the Therapeutic Range, the oral multiple dose equations would also. The two modifications would be to the Dose. Bioavailability, f, must be considered, and if the drug given is not the drug measured in the blood, the salt factor, S, the difference in the molecular weight of the two compounds must be taken into account, (i.e.

MW measured S = -----------------------------MW given

). Thus, when amino-

phyline, which is a complex consisting of two theophyline molecules and an ethylinedyamine molecule is given, but theophyline is measured, the salt factor, MW Theo 2 ⋅ 180.17 - = ------------------------ = 0.857 S = ----------------------MW Amino 420.44

. Thus for oral multiple dose, we can approximate

for using IV bolus equations as such : Cp max

Cp

ss avg

ss

S⋅f⋅D 1 = ------------------ ⋅ --------------------N V 1 –  1---   2

S⋅f⋅D S⋅f⋅D 1.443 ⋅ S ⋅ f ⋅ D = ------------------- = ------------------------------ = -----------------------------------V ⋅ K ⋅ τ V ⋅ 0.693 ⋅ N N⋅V

(EQ 10-16)

(EQ 10-17)

N

Cp min

ss

 1---  2 S⋅f⋅D = ------------------ ⋅ --------------------V 1 N 1 –  ---  2

(EQ 10-18)

because errors involved with this approximation both in maximum and minimum calculations (peak and trough) place the drug further within the Therapeutic Range, i.e. the real peaks are lower than the calculated peaks and the real troughs are higher than the calculated troughs, thus both errors are on the side of safety. Dosing Interval

The object of pharmacokinetics is to optimize therapy. By definition, that is to maintain the plasma concentration of the drug within the therapeutic range for the duration of the therapy presuming that is needed. Thus, the concentrations must stay within the MTC and MEC or ss

Cp max N MTC-----------= ------------------= 2 max ss MEC Cp min

(EQ 10-19)

by deviding equation 10-18 into equation 10-16 and simplifying. Given these limits, the maximum dosing interval, τmax , is obtained by solving for Nmax:

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Dosage Regimen (Healthy, Aged, and Diseased Patients)

N max and since

τ max N max = ---------t1 ⁄ 2

MTC- Ln  -----------MEC = -------------------------Ln2

(EQ 10-20)

by definition, τ max = N max ⋅ t1 ⁄ 2

(EQ 10-21)

τ max

is not necessarily the dosing interval of choice, but it is the maximum dosing interval attainable without sustained or controlled release delivery systems. Accepable dosing intervals are those which result in a dose being given at the same time of the day, every day. Imagine, if you will, the chaos on the nursing floor if the dose for a given drug were every 15 hours. Compliance, none too high when the patient is given a reasonable dosing interval, would go straight to the toilet if we asked the patient to take a tablet every 5.3 hours. What would be optimal would be to tie the takeing of the drug with an activity that occurs the same time every day for once a day therapy, or at least dose the same time every day. Thus, for multiple daily doses, the only regimens that work are those which when devide into 24 hours give unit answers: QD = 24/1 = q24h; BID = 24/2 = q12h, TID = 24/ 3 = q8h; QID = 24/4 = q6h; q4h; q3h; q2h. These result in decreasing orders of patient compliance (unless the patient is really motivated to take the drug every 2 hours - forget it.) Thus the maximum acceptable dosing interval would be the largest acceptable dosing interval below the τ max . So, for example if τ max is 15.7 hours, the maximum acceptable dosing interval would be 12 hours. we could also dose every 8, 6 or 4 hours if necessary.

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10-9

Dosage Regimen (Healthy, Aged, and Diseased Patients)

10.2 Diseases - Dosing the Compromised Patient As previously discussed in the chapter on clearance, diseases result in changes in clearance. These are routinely as a consequence of changes in organ function or blood flow to the organ. Diseases which cause a change in clearance, do so by changing either the elimination rate constant, K, or the volume of distribution, Vd, or both. Thus the fractional change in total body clearance : Cl tot ∗ K∗ ⋅ V∗ F Cl tot = -------------= -----------------K⋅V Cl tot Where X* indicates new or changed variable.

(EQ 10-22)

In general, if

0.80 < F Cl < 1.2 , tot

changes in dosage regimen are not necessary. In order to return a previously controlled healthy pateint back to the therapeutic range, a general rule of thumb is suggested as an initial starting point. The desease modifies K (as t1/2) and V. As pharmacists, we can modify D and τ . These variables are paired in the above equations (equation 10-16 and equation 10-18), D with V (in with

τ

(in

τ N = --------t1 ⁄ 2

S----------------⋅ f ⋅ DV

) and

t1 ⁄ 2

). If the physiological change is a change in V, the pharmacist

would recommend a change in D proportionally, and if the half life changes, the pharmacist would recommend a change in the dosing interval proportionally. Remenber, the object is to get the plasma concentrations back to where they were prior to the illness. The only problem is that we are limited to these recommended changes being incremental and not continuous. That is a change in dose is limited to the available dosage forms and strengths and a change in dosing interval is limeted to the accepatable dosing interval. Protein Binding

If the drug is highly protein bound, the object would be to get the free concentration back to what it was prior to illness. Consequently, equation 10-16, equation 10-17, and equation 10-18 would be rewritten thus: Cp

Cp

ss fu ⋅ S ⋅ f ⋅ D ss 1 = f u ⋅ Cp = -------------------------⋅ -------------------N V max free max 1 –  1--- 2

ss fu ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D ss = fu ⋅ C p = -------------------------= -----------------------------V⋅K⋅τ V ⋅ 0.693 ⋅ N avg free avg

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(EQ 10-23)

(EQ 10-24)

10-10

Dosage Regimen (Healthy, Aged, and Diseased Patients)

N

Cp

ss min free

 1---  2 fu ⋅ S ⋅ f ⋅ D ss = fu ⋅ Cp = -------------------------- ⋅ -------------------N V min 1 –  1--- 2

(EQ 10-25)

Some interesting and unexpected things result from these relationships. Since plasma or blood concentrations are usually measured, if a drug is highly protein bound and the desease results in upsetting that equilibrium, you might see toxicity resulltling from normal or even subtherapeutic measured concentrations. More on that in the chapter on protein binding.

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Dosage Regimen (Healthy, Aged, and Diseased Patients)

10.3 Problems

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10-12

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Alprazolam Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 1)

AHFS 00:00.00 GPI: 0000000000

Juhl, R. et al., "Alprazolam pharmacokinetics in alcoholic liver disease", Journal of Clinical Pharmacology, Vol.24, (1984), p. 113 - 119.

Alprazolam is an anti-anxiety agent which is metabolized to 4-hydroxy and α-hydroxy metabolites. In this study, patients with cirrhosis of the liver and healthy patients were each given doses of 1.0 mg of Alprazolam. The following data is for healthy patients. PROBLEM TABLE 10 - 1.

Alprazolam

Dose

1.0 mg BID 1.16 L/kg 1.22 529.3

AUC

Assume that your patient weighs 70 kg when answering the following: 1.

Find k.

2.

Find the MRT.

3.

Find the .

4.

Find the AUMC.

5.

Find τ.

6.

What is N?

7.

What is the patient's maximum plasma concentration, , under this dosage regimen.

8.

What is the patient's average plasma concentration, , under this dosage regimen.

9.

What is the patient's minimum plasma concentration, , under this dosage regimen.

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10-13

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Cefixime Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 2)

AHFS 00:00.00 GPI: 0000000000

Faulkner, R. et al., "Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state", Journal of Clinical Pharmacology, Vol.27, (1987), p. 807 - 812.

Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bacteria. In this study, patients received a 200 mg oral dose of cefixime twice daily. PROBLEM TABLE 10 - 2.

Cefixime

Dose

200 mg BID 3.3 hours 286 32

AUC

14.12

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

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10-14

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Cefpodoxime Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 3)

AHFS 00:00.00 GPI: 0000000000

Borin, M. et. al., "Pharmacokinetics and tolerance studies of cepodoxime after single-and multiple-dose oral administration of cefpodoxime proxetil", Journal of Clinical Pharmacology, Vol.31, (1991), p. 1137 - 1145.

Cefpodoxime proxetil is a third-generation, broad-spectrum cephalosporin which is given by the oral route. It is a prodrug which is converted in vivo to cefpodoxime which inhibits bacterial cell wall synthesis by binding to penicillinbinding proteins. PROBLEM TABLE 10 - 3.

Cefpodoxime

Dose

100 mg BID 2.1 hours 271 79.1

AUC

6.9

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

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10-15

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Cefprozil Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 4)

AHFS 00:00.00 GPI: 0000000000

Lode, H. et. al., "Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers", Antimicrobial Agents and Chemotherapy, Vol.36, (1992), p. 144 - 149.

Cefprozil is a broad-spectrum cephalosporin which is given by the oral route. In this study subjects received 500 mg doses of cefprozil every twelve hours for eight days. PROBLEM TABLE 10 - 4.

Cefprozil

Dose

500 mg q. 12 hours 55.11minutes 310.25 277.50

AUC

27.80

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

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10-16

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Clobazam Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 5)

AHFS 00:00.00 GPI: 0000000000

Greenblatt, D. et. al., "Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.

Clobazam is an agent used in the treatment of anxiety. In this study, patients received 10 mg dose of clobazam daily. PROBLEM TABLE 10 - 5. Clobazam

Dose

10 mg daily 180 hours

AUC

1.

Find k.

2.

Find MRT.

3.

Find the ?

4.

Find the AUMC.

5.

Find τ.

6.

What is N?

7.

What is the patient's maximum plasma concentration, , under this dosage regimen.

8.

What is the patient's average plasma concentration, , under this dosage regimen.

9.

What is the patient's minimum plasma concentration, , under this dosage regimen.

10. Your patients renal function drops to 50% of normal. What would be a new dosing regimen under these conditions? (Assume that you want to keep < 110% of the normal and that you want to keep > 90% of the normal .)

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Maloprim

(Problem 10 - 6)

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

AHFS 00:00.00 GPI: 0000000000

Edstein, M., Rieckmann, K., and Veenendaal, J., "Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man", British Journal of Clinical Pharmacokinetics, Vol.30, (1990), p.259 - 265.

Maloprim is an agent which contains both dapsone and pyrimethamine. In this study, healthy volunteers were given 100 mg of dapsone plus 12.5 mg pyrimethamine weekly. The following data is for dapsone: PROBLEM TABLE 10 - 6. Maloprim

Dose

100 mg weekly 22.6 hours

AUC

35.0

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-18

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Doxycycline

(Problem 10 - 7)

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

AHFS 00:00.00 GPI: 0000000000

Shmuklarsky, M. et. al., "Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy nonimmune volunteers", Annals of Internal Medicine, Vol.120, (1994), p. 294 - 298.

Doxycycline is an antibiotic which has been recommended for prevention of malaria in people traveling to areas endemic to chloroquine-resistant P. falciparum malaria who are unable to take mefloquine. This study determined that doxycycline is not effective for this use. Volunteers were given 100 mg doses of doxycycline daily for 10 days. PROBLEM TABLE 10 - 7.

Doxycycline

Dose

100 mg daily 21.9 hours

AUC

40.7

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-19

Dosage Regimen (Healthy, Aged, and Diseased Patients)

DQ-2556 Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 8)

AHFS 00:00.00 GPI: 0000000000

Nakashima, M. et. al., "Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic", Journal of Clinical Pharmacology, Vol.33, (1993), p. 57 - 62.

DQ-2556 is a new broad-spectrum cephalosporin which is active against many bacteria including Pseudomonas aeruginosa. Subjects in this study were each given a 2000 mg infusion of DQ-2556 over 5 minutes every 12 hours for a total of 9 doses. PROBLEM TABLE 10 - 8.

DQ-2556 Dose

2000 mg infusion over 5 minutes 17.6 L 8.5 7.1

AUC

241.0

1.

Find Cl.

2.

Find k.

3.

Find the MRT.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-20

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Erythropoetin Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 9)

AHFS 00:00.00 GPI: 0000000000

Gladziwa, U., et al., "Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients undergoing haemodialysis and haemofiltration", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.

Erythropoetin is a regulatory hormone of red blood cells. In this study patients with end-stage renal disease were given 150 U/kg of epoetin three times a week. PROBLEM TABLE 10 - 9.

Glipizide

Dose

150 U/kg t.i.w. 7.7hours

Cl

5.4

Assuming that your patient weighs 65 kg, please determine the following: 1.

Find k.

2.

Find MRT.

3.

Find the .

4.

Find the AUC.

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-21

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Flecainide Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 10)

AHFS 00:00.00 GPI: 0000000000

Forland, S. et al., "Flecainide pharmacokinetics after multiple-dosing in patients with impaired renal function", Journal of Clinical Pharmacology, Vol.28, (1988), p. 727 - 735.

Flecainide acetate is a class 1C anti-arrhythmic agent which is used in the treatment of ventricular and supraventricular arrhythmias. In this study, subjects were given doses of 100mg of flecainide orally twice daily. PROBLEM TABLE 10 - 10. Flecainide

Dose

100 mg BID 7.4 L/kg 486 89

AUC

3.429

Assume that your patient weighs 70 kg when calculating the following: 1.

Find Cl.

2.

Find k.

3.

Find the MRT.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-22

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Glipizide Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 11)

AHFS 00:00.00 GPI: 0000000000

Kradjan, W. et al., "Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing", Journal of Clinical Pharmacology, Vol.29, (1989), p. 1121 - 1127.

Glipizide is a second-generation oral hypoglycemic agent used in the treatment of non-insulin-dependent (type II) diabetes. In this study, both diabetic and non-diabetic elderly men were each given doses of 2.5 mg of glipizide daily for five days. The data for the non-diabetic group is given below. PROBLEM TABLE 10 - 11.

Dose

2.5 mg daily 4.0 hours 0.47

AUC

2325.4

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-23

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Lomefloxacin Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 12)

AHFS 00:00.00 GPI: 0000000000

Hunt, T. and Adams, M., "Pharmacokinetics and safety of lomefloxacin following multiple doses", Diagn Microbiol Infect Dis, Vol.12, (1989), p. 181 - 187.

Lomefloxacin is a quinolone antibiotic which is useful against both Gram-positive and Gram-negative bacteria. It is used in the treatment of urinary tract infections and lower respiratory tract infections. A dose of 400 mg of lomefloxacin was given twice daily to healthy patients. PROBLEM TABLE 10 - 12. Lomefloxacin

Dose

400 mg BID 7.32 hours

AUC

61.67

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-24

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Loratadine Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 13)

AHFS 00:00.00 GPI: 0000000000

Radwanski, E. et al., "Loratadine: multiple-dose pharmacokinetics", Journal of Clinical Pharmacology, Vol.27, (1987), p. 530 533.

Loratadine is an antihistamine which is orally active. In this study, healthy, male volunteers were each given a 40-mg loratadine capsule daily for ten days. PROBLEM TABLE 10 - 13. Loratadine

Dose

40 mg daily 14.4 hours

AUC

96.0

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-25

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Methamphetamine Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 14)

AHFS 00:00.00 GPI: 0000000000

Cook, C., et al., "Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans", Drug Metabolism and Disposition, Vol.20, (1992), p. 856 - 861.

Methamphetamine is a CNS stimulant which is used in the treatment of attention deficit disorder and obesity. In this study, subjects were given a 0.125 mg/kg dose of methamphetamine daily. PROBLEM TABLE 10 - 14. Methamphetamine

Dose

0.125 mg/kg daily 8.46 hours 65.0 212

Assume that your patient weighs 70 kg when calculating the following: 1.

Find k.

2.

Find MRT.

3.

Find the .

4.

Find the AUC.

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-26

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Mexiletine Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 15)

AHFS 00:00.00 GPI: 0000000000

Gillis, A. and Kates, R., "Clinical pharmacokinetics of the newer antiarrhythmic agents", Clinical Pharmacokinetics, Vol.9, (1984), p. 375 - 403.

Mexiletine is a class Ib antiarrhythmic agent. In this study, volunteers each received a 1600 mg dose orally each day. PROBLEM TABLE 10 - 15. Mexiletine

Dose

1600 mg daily 380 L 681

1.

Find k.

2.

Find the MRT.

3.

Find the .

4.

Find the AUC.

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-27

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Moxisylyte Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 16)

AHFS 00:00.00 GPI: 0000000000

Costa, P. et al., "Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers", Journal of Pharmaceutical Sciences, Vol.82, (1993), p. 968 - 971.

Moxisylyte is an α-adrenergic blocker which has been used in Europe for some times as a vasodilator in the treatment of such disease states as age-associated mental impairment, acrocyanosis, Raynaud's syndrome, vascular cochlearvestibular disorders, glaucoma, and benign prostatic hyperplasia. PROBLEM TABLE 10 - 16. Moxisylyte

Dose

240 mg BID 2.28 hours

AUC

11186

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-28

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Naproxen Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 17)

AHFS 00:00.00 GPI: 0000000000

Ouweland, F. et. al., "Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritis", Clinical Pharmacokinetics, Vol.11, (1986), p. 511 - 515.

The pharmacokinetics parameters of naproxen were looked at in patients with rheumatoid arthritis in this study. A patient received a dose of 500 mg of naproxen orally twice daily. PROBLEM TABLE 10 - 17. Naproxen

Dose

500 mg BID 9.0 L

AUC

1134

1.

Find Cl.

2.

Find k.

3.

Find the MRT.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-29

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Nisoldipine Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 18)

AHFS 00:00.00 GPI: 0000000000

Harten, J. et al., "Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single and multiple dosing", Clinical Pharmacokinetics, Vol.16, (1989), p. 55 - 64.

Nisoldipine is a second-generation calcium-channel blocker which is under investigation for use as an anti-hypertensive agent. Nisoldipine is mainly eliminated through liver metabolism with metabolites being excreted mainly in the urine but also in the feces. The systemic clearance of nisoldipine depends greatly on liver blood flow. PROBLEM TABLE 10 - 18. Nisoldipine

Dose

10 mg BID orally 7.9 hours

AUC

5.2

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the ?

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-30

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Pefloxacin Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 19)

AHFS 00:00.00 GPI: 0000000000

Bruno, D. et al., "Bayesian versus NONMEM estimation", , Vol. , (19 ), p. 657 - 668.

Pefloxacin is an antibiotic used to treat patients who are in the intensive care unit. For this study, patients were given a 400 mg dose of pefloxacin twice daily for eight days. PROBLEM TABLE 10 - 19. Pefloxacin

Dose

400 mg BID 21.3 hours

Cl

3.77

1.

Find k.

2.

Find MRT.

3.

Find the ?

4.

Find the AUC.

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-31

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Phenylpropanolamine Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 20)

AHFS 00:00.00 GPI: 0000000000

Scherzinger, S., Rowse, R., and Kanfer, I., "Steady state pharmacokinetics and dose-proportionality of phenylpropanolamine in healthy subjects", Journal of Clinical Pharmacology, Vol.30, (1990), p. 372 - 377.

Phenylpropanolamine is a sympathomimetic agent which is used both for its action as a nasal decongestant and its action as an anorexiant. In this study healthy volunteers were given doses of 25 mg every four hours for a total of seven doses. It was found that phenylpropanolamine is 77% renally excreted. PROBLEM TABLE 10 - 20. Phenylpropanolamine

Dose

25 mg q. 4 hours 4.71 hours 4.08 L/kg 0.5

1.

Find k.

2.

Find MRT.

3.

Find Cl.

4.

Find the AUC.

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-32

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Promethazine Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 21)

AHFS 00:00.00 GPI: 0000000000

Taylor, G. and Houston, J., "Changes in the disposition of promethazine during multiple dosing in rabbits", Journal of Clinical Pharmacology, Vol.37, (1985), p. 243 - 247.

Promethazine is an agent used as an anti-histamine and a sedative. In this study rabbits weighing 2.7 to 3.3 kilograms each received a 10 mg/kg dose of promethazine every 24 hours for 14 days. PROBLEM TABLE 10 - 21. Promethazine

Dose

10 mg/kg 249 minutes 65.0

1.

Find k.

2.

Find MRT.

3.

Find the ?

4.

Find the AUC.

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-33

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Rufloxacin Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 22)

AHFS 00:00.00 GPI: 0000000000

Mattina, R. et al., "Pharmacokinetics of rufloxacin in healthy volunteers after repeated oral doses", Chemotherapy, Vol.37, (1991), p. 389 - 397.

Rufloxacin is a broad-spectrum, fluoroquinolone antibiotic. In this study a patient was given a loading dose of 300 mg of rufloxacin followed by 150 mg of rufloxacin daily for five days. PROBLEM TABLE 10 - 22. Rufloxacin

Dose

150 mg daily 104 L 41 10

AUC

121.5

1.

Find k.

2.

Find the MRT.

3.

Find the .

4.

Find the AUMC.

5.

Find τ.

6.

What is N?

7.

What is the patient's maximum plasma concentration, , under this dosage regimen.

8.

What is the patient's average plasma concentration, , under this dosage regimen.

9.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-34

Dosage Regimen (Healthy, Aged, and Diseased Patients)

Velnacrine (HP 029) Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long

(Problem 10 - 23)

AHFS 00:00.00 GPI: 0000000000

Puri, S. et al., "Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a potential therapeutic agent for Alzheimer's disease", Journal of Clinical Pharmacology, Vol.30, (1990), p. 948 - 955.

Velnacrine is an investigative agent which has central cholinergic action and may be beneficial in the treatment of Alzheimer's disease. Healthy, elderly, men were given doses of 100 mg twice daily in this study. It was found that 30% of the velnacrine dose was excreted unchanged. PROBLEM TABLE 10 - 23. Velnacrine

Dose

(HP 029)

100 mg BID 2.4 hours

AUC

809.5

1.

Find k.

2.

Find the MRT.

3.

Find Cl.

4.

Find the .

5.

Find the AUMC.

6.

Find τ.

7.

What is N?

8.

What is the patient's maximum plasma concentration, , under this dosage regimen.

9.

What is the patient's average plasma concentration, , under this dosage regimen.

10.

What is the patient's minimum plasma concentration, , under this dosage regimen.

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-35

Dosage Regimen (Healthy, Aged, and Diseased Patients)

10.4 Answers Alprazolam 1.

0.0631 h-1

2.

15.85 hours

3.

10.98 hours

4.

8387.81

5.

12

6.

1.093

7.

23.19

8.

16.26

9.

10.876

Cefixime 1.

0.210 h-1

2.

4.76 hours

3.

14.164 L/h

4.

67.435 L

5.

62.224

6.

12

7.

3.64

8.

3.225

9.

1.177

10.

0.259

Cefpodoxime 1.

0.330 h-1

2.

3.03 hours

3.

14.49 L/h

4.

43.91 L

5.

20.905

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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10-36

Dosage Regimen (Healthy, Aged, and Diseased Patients)

6.

12

7.

5.714

8.

2.322

9.

0.575

10.

0.0442

Cefprozil 1.

0.0126 min-1

2.

76.51 minutes

3.

17.99 L/h

4.

23.83 L

5.

36.84

6.

12

7.

13.065

8.

20.98

9.

2.317

10.

2.45

Maloprim 1.

0.0307 h-1

2.

32.6 hours

3.

2.857 L/h

4.

93.16 L

5.

1141.17

6.

168

7.

7.435

8.

1.08

9.

0.208

10.

6.25

Doxycycline 1.

0.0317 h-1

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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10-37

Dosage Regimen (Healthy, Aged, and Diseased Patients)

2.

31.595 hours

3.

2.457 L/h

4.

77.629 L

5.

1285.92

6.

24

7.

1.096

8.

2.42

9.

1.696

10.

1.133

DQ-2556 1.

8.299 L/h

2.

0.4715 h-1

3.

2.12 hours

4.

1.47 hours

5.

511.11

6.

12

7.

8.163

8.

114

9.

20.083

10.

0.398

Erythropoetin 1.

0.09 h-1

2.

11.11 hours

3.

3599.24 mL

4.

30092.6

5.

334291.14

6.

72

7.

9.35

8.

2713.24

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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10-38

Dosage Regimen (Healthy, Aged, and Diseased Patients)

9.

417.98

10.

4.156

Glipizide 1.

0.173 h-1

2.

5.77 hours

3.

1.075 L/h

4.

6.204 L

5.

13419.37

6.

24

7.

6

8.

0.4094

9.

96.893

10.

6.396

Flecainide 1.

29.16 L/h

2.

0.0563 h-1

3.

17.76 hours

4.

12.31 hours

5.

60.91

6.

12

7.

0.975

8.

0.393

9.

0.286

10.

0.200

Lomefloxacin 1.

0.0947 h-1

2.

10.56 hours

3.

6.486 L/h

4.

68.497 L

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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10-39

Dosage Regimen (Healthy, Aged, and Diseased Patients)

5.

651.27

6.

12

7.

1.639

8.

8.6

9.

5.139

10.

2.76

Loratadine 1.

0.0481 h-1

2.

20.77 hours

3.

416.67 L/h

4.

8656.17 L

5.

1994.38

6.

24

7.

1.67

8.

6.746

9.

4

10.

2.125

Methamphetamine 1.

0.082 h-1

2.

12.21 hours

3.

46.7 L

4.

2.244

5.

27.383

6.

24

7.

2.837

8.

213.74

9.

93.48

10.

29

Moxisylyte

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-40

Dosage Regimen (Healthy, Aged, and Diseased Patients)

1.

0.304 h-1

2.

3.29 hours

3.

0.0215 L/h

4.

70.574 mL

5.

36794.61

6.

12

7.

5.263

8.

3.492

9.

0.9322

10.

0.0909

Naproxen 1.

0.441 L/h

2.

0.049 h-1

3.

20.412 hours

4.

14.149 hours

5.

23147.21

6.

12

7.

0.848

8.

124.98

9.

94.5

10.

69.43

Mexiletine 1.

0.1075 h-1

2.

9.3 hours

3.

6.45 hours

4.

39.16

5.

364.17

6.

24

7.

3.723

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-41

Dosage Regimen (Healthy, Aged, and Diseased Patients)

8.

4.256

9.

1.632

10.

0.345

Nisoldipine 1.

0.0877 h-1

2.

11.397 hours

3.

1923.08 L/h

4.

21.92 mL

5.

59.27

6.

12

7.

1.52

8.

700.7

9.

433.3

10.

244.5

Pefloxacin 1.

0.0325 h-1

2.

30.73 hours

3.

115.85 L

4.

106.1

5.

3260.4

6.

12

7.

0.563

8.

10.68

9.

8.84

10.

7.23

Phenylpropanolamine 1.

0.147 h-1

2.

6.795 hours

3.

36.03 L/h

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-42

Dosage Regimen (Healthy, Aged, and Diseased Patients)

4.

0.694

5.

4.715

6.

4

7.

0.849

8.

229.5

9.

173.5

10.

127.4

Promethazine 1.

0.167 h-1

2.

5.987 hours

3.

70.05 L

4.

2.56

5.

15.35

6.

24

7.

5.78

8.

436.19

9.

106.84

10.

7.92

Rufloxacin 0.0237 h-1 42.28 hours 29.30 hours 5136.6 24 0.819 3.33 2.54 1.89 Velnacrine

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-43

Dosage Regimen (Healthy, Aged, and Diseased Patients)

1.

0.289 h-1

2.

3.462 hours

3.

123.53 L/h

4.

427.73 L

5.

2802.87

6.

12

7.

5

8.

241.33

9.

67.46

10.

7.54

Basic Pharmacokinetics

REV. 99.4.25

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

http://kiwi.creighton.edu/pkinbook/

10-44