Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation.
There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)-coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP-glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean +/- SD [% coefficient of variation [CV]) were 7.3 +/- 2.8 (39%), 31.9 +/- 33.6 (106%), and 16.4 +/- 5.8 (35%) mL/min/kg, respectively, whereas half-life values were 4.2 +/- 1.9 (46%), 8.1 +/- 7.9 (98%), and 1.5 +/- 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein in UGT2B7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB-coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance.
Kwara
Awewura
A
Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. akwara@lifespan.org
Lartey
Margaret
M
Boamah
Isaac
I
Rezk
Naser L
NL
Oliver-Commey
Joseph
J
Kenu
Ernest
E
Kashuba
Angela D M
AD
Court
Michael H
MH
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy; D000328:Adult; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D016568:Drugs, Generic / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005869:Ghana; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006207:Half-Life; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018119:Stavudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy / Q000209:etiology; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D004338:Drug Combinations; D016568:Drugs, Generic; D020719:Glucuronides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D018119:Stavudine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase