Basic Pharmacokinetics - Tamide Exam

::

Tolbutamide

(Problem 1)

Miners J, Foenander T, Wanwimolruk S, Gallus A, Birkett D. (European Journal of Clinical Pharmacology) The effect of sulphinpyrazone on oxidative drug metabolism in man: inhibition of tolbutamide elimination (1982) 22: 321-326.

About the drug: Tolbutamide is a sulfonylurea which has been used as an oral hypoglycemic agent in noninsulin-dependent Diabetes Miletus with adult onset. In a study using normal, healthy, 70 kg volunteers the following pharmacokinetic data was obtained. Tolbutamide is well absorbed. It is highly protein bound (96%). The volume of distribution is 0.143 L/kg with a half-life of 6.93 hours in normal adults. Tolbutamide is cleared entirely by hepatic function. Dosing: Tolbutamide (Orinase-brand name) is manufactured by Upjohn. Both 250 and 500 mg tablets are manufactured. Both tablet sizes are available for prescription use. The normal daily dose should not exceed 3 grams. Your consult should contain both an aggressive and conservative dosage regimen recommendations when appropriate as well as calculations where appropriate. Extraction ratios are calculated for normal individuals and are considered to be constant. Qr = 0.0191 L/min/kg, Qh = 0.0238 L/min/kg. Bioequivalence: In a study presented to you (Int J Clin Pharmacol Ther 1997 Jan; 35(1):43-6) A 500 mg brand name tablet yielded an AUC of 499 mg/L *hr while a 500 mg generic tablet yielded an AUC of 498 mg/L *hr . The Cpmaxs were 55.1 vs 58.8 mic/mL and the Tmaxs were 4.55 vs 3.82 hr respectively. The generic comes in 250 and 500 mg scored tablets and cost approximately 1/3 of the brand name. You have been asked to prepare a recommendation for the P & T Committee for inclusion into the formulary for the HMO. Please give your recommendation and support it with appropriate documentation. (Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics

REV. 98.10.22

Copyright © 1996 Michael C. Makoid All Rights Reserved

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

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Elderly: Tolbutamide is mainly used for the treatment of middle aged and elderly patients. It is well documented that plasma albumen levels decrease with increasing age. This produces a net decrease in protein binding equivalent to 92%, with no change in drug half-life or volume of distribution. Please prepare an initial consult for KT a 75 y/o, 70 kg, healthy male. Your consult should contain both an aggressive and conservative dosage regimen recommendation which attempts to attain the free tolbutamide concentration range of normal, healthy volunteers who were dosed at 250 mg TID as well as a short explanation of the observations. (Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations) Basic Pharmacokinetics

REV. 98.10.22

Copyright © 1996 Michael C. Makoid All Rights Reserved

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

-2

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Concomitant treatment: Sulphinpyrazone, a drug used as an antithrombotic agent and inhibitor of platelet aggregation has a potent side effect as a uricosuric agent. The uricosuric side effect increases the urinary excretion of uric acid effectively blocking hepatic conjugation. Tests show that Sulphinpyrazone’s effect on Tolbutamide is a reduction of liver function (Clinth*/Clinth = 0.6) to 60% of normal without interfering with protein binding. Please prepare a dosage regimen consult for LM, an otherwise normal, 90 kg adult who was maintained on 250 mg Orinase QID prior to taking this new drug as well as a short explanation of the observations. (Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics

REV. 98.10.22

Copyright © 1996 Michael C. Makoid All Rights Reserved

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

-3

::

Systemic Alkalosis: Gastric acid loss caused by vomiting is a concern for the hypoglycemic patient using Tolbutamide. Tolbutamide’s molecular structure contains an active sulfonamide group which ionizes at increased plasma pH levels associated with metabolic alkalosis from gastric acid loss in vomition. Because of this ionization Tolbutamide protein binding to alpha1-acid glycoprotein is increased to 98%, with a decrease in volume of distribution to 6.375 L. Please prepare a dosage regimen consult for AM, an otherwise normal, 80 kg adult who was maintained on 250 mg Orinase TID prior to this problem as well as a short explanation of the observations. . (Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics

REV. 98.10.22

Copyright © 1996 Michael C. Makoid All Rights Reserved

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

-4

::

Viral Hepatitis: Viral hepatitis causes a 72.5% increase in volume of distribution while and decreasing the protein binding to 92% and the hepatic function by 25% (Clinth*/Clinth = 0.75). Please prepare a dosage regimen consult for BE, an otherwise normal, 55 kg adult who was maintained on 250 mg Orinase BID prior to this problem as well as a short explanation of the observations.. (Short paragraph)

(Important variables and constants)

(Use other side for supportive documentation - appropriate calculations)

Basic Pharmacokinetics

REV. 98.10.22

Copyright © 1996 Michael C. Makoid All Rights Reserved

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

-5

::

161) Are the tablets bioequivalent? Why/ Why not? Patient Condition

Normal

Dose(mg)

500 mg IV

500 mg Brand tablet

Elderly

Concomitant Treatment

Systemic Alkylosis

Viral Hepatitis

500 mg Generic tablet

72) ??? mg tablet

92) ??? mg tablet

115) ??? mg tablet

138)??? mg tablet

f

1)

22)

49)

73)

93)

116)

139)

fu

2)

23)

50)

74)

94)

117)

140)

Vd (L)

3)

24)

51)

75)

95)

118)

141)

k (hr-1)

4)

25)

52)

76)

96)

119)

142)

T 1/2 (hr)

5)

26)

53)

77)

97)

120)

143)

6)

27)

54)

78)

98)

121)

144)

7)

28)

55)

8)

29)

56)

MAT

30)

57)

Ka

31)

58)

AUC (mg/L*hr) AUMC (mg/L*hr

2)

MRT

Peak Time

9)

32)

59)

Cl tot (L/hr)

10)

33)

60)

79)

99)

122)

145)

Cl h (L/hr)

11)

34)

61)

80)

100)

123)

146)

Cl r (L/hr)

12)

35)

62)

81)

101)

124)

147)

Eh

13)

36)

63)

82)

102

125)

148)

Er

14)

37)

64)

83)

103)

126)

149)

(L/hr)

15)

38)

65)

84)

104)

127)

150)

(L/hr)

16)

39)

66)

85)

105)

128)

151)

FR h

17)

40)

67)

85)

106

129)

152)

FI h

18)

41)

68)

87)

107)

130)

153)

FR r

19)

42)

69)

73)

108)

131)

154)

FI r

20)

43)

70)

77)

109)

132)

155)

FCL

21)

44)

71)

81)

110)

133)

156)

Cl h Cl r

int

int

τ (hr)

45)

85)

111)

134)

157)

N

46)

89)

112)

135)

158)

µg-  ------max f ree  mL

47)

90)

113)

136)

159)

Cp

µg-  ------min free  mL

48)

91)

114)

137)

160)

Cp

ss

ss

Basic Pharmacokinetics

REV. 98.10.22

Copyright © 1996 Michael C. Makoid All Rights Reserved

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

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