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

Abstract

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.

Figure 1

Mean steady-state plasma concentration-time profiles of lamivudine, zidovudine and stavudine in HIV/TB co-infected patients during concurrent HIV and TB therapy. Of the 27 total patients studied, 16 patients received the lamivudine with zidovudine (fixed dose combination) and 11 patients received lamivudine with stavudine. Error bars indicate standard error of the mean.

Figure 2

Relationship between apparent oral clearance of lamivudine normalized for body weight and the age of HIV/TB co-infected patients receiving lamivudine, with zidovudine or stavudine. All the patients received efavirenz, 4-drug TB therapy, as well as trimethoprim-sulfamethoxazole.

Figure 3

Effect of UGT2B7*1c allele on mean (±SE) zidovudine concentration-time profile (A) and body weight normalized apparent oral clearance (B). Differences between carrier and non-carrier groups were evaluated by Mann-Whitney rank sum test. Horizontal bars represents median.

Figure 4

Effect of UGT2B7*1c allele on glucuronidation of zidovudine (A), relative UGT2B7 protein content in human liver microsomes (B) and relative mRNA (C). Differences between carrier and non-carrier groups were evaluated by unpaired t-test (protein and mRNA), or by Mann-Whitney rank sum test (zidovudine glucuronidation).

Figure 5

Effect of UGT2B7 genotype on liver zidovudine glucuronidation activity. Bars represent mean ± SD values and group differences were evaluated by ANOVA.