Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection

Abstract

The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects >18 to <25 years old receiving (>28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC 0-24 ), maximum concentration of drug in serum (C max ), concentration at 24 h postdose (C 24 ), and total apparent oral clearance (CL/F) values were 35,971 ng ⅐ hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC 0-24 , C max , C 24 , and CL/F values were 2,762 ng ⅐ hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C max and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.

Steady-State Pharmacokinetics of Tenofovir-Based Regimens in HIV-Infected Pediatric Patients

“…In contrast, we found that the GMs (90% CI) for tenofovir AUC and C min in the presence of atazanavir-ritonavir were only slightly above the target upper limit and the median tenofovir AUC and C max were similar to what is described for patients not receiving concurrent atazanavir and ritonavir (6). However, tenofovir AUC and C min were higher than those reported in 22 HIV-infected young adults Ն18 to Ͻ25 years of age who received concomitant atazanavir and ritonavir (9). The authors suggested that the lower tenofovir exposure seen in their adolescent population may be due to faster tenofovir clearance (49.2 liters/h).…”

Steady‐state amprenavir and tenofovir pharmacokinetics after coadministration of unboosted or ritonavir‐boosted fosamprenavir with tenofovir disoproxil fumarate in healthy volunteers

“…In previous TDF-FPV/RTV coadministration studies, the effect of adding an FPV regimen to a TDF regimen was not evaluated. However, two studies that evaluated APV pharmacokinetics following the addition of TDF 300 mg qd to an FPV/RTV 700/100 mg bid or 1400/200 mg qd regimen noted negligible increases in steady-state APV APV and TFV pharmacokinetic changes observed in our study were unlikely to be clinically important because the steady-state geometric mean TFV C min remained within the range reported in HIV-infected patients treated with TDF 300 mg qd without concurrent FPV [22][23][24], and the geometric mean APV C min for unboosted FPV (0.351 mg/ mL) and FPV/RTV (2.88 mg/mL) during TDF coadministration remained 2.4-and 19.7-fold higher than the documented protein binding-adjusted 50% inhibitory concentration (IC 50 ) for wild-type HIV isolates (0.146 mg/mL), respectively [25].The pattern of plasma C min and AUC changes that we observed during TDF-FPV and TDF-FPV/RTV coadministration was different from the pattern reported when TDF was given with ATV [10,26], ATV/RTV [10,11,27], LPV/RTV [12,13,24,28] or indinavir (IDV) [13] (increase in TFV and decrease in PI), DRV or brecanavir (BCV) (increase in TFV and PI) [14,29], nelfinavir (NFV) (no change in TFV and decrease/no change in NFV and/or active metabolite M8) [30,31], saquinavir (SQV) (increase in TFV and increase/no change in SQV) [22,32], or TPV/RTV (no change/increase in TFV and decrease in TPV) [33]. Interactions between TDF and PIs can potentially occur at the kidney and/or the gut level.…”

“…However, two studies that evaluated APV pharmacokinetics following the addition of TDF 300 mg qd to an FPV/RTV 700/100 mg bid or 1400/200 mg qd regimen noted negligible increases in steady-state APV C min values (by 4% [15] and 2% [19], respectively). The Fosamprenavir-tenofovir interaction 195 APV and TFV pharmacokinetic changes observed in our study were unlikely to be clinically important because the steady-state geometric mean TFV C min remained within the range reported in HIV-infected patients treated with TDF 300 mg qd without concurrent FPV [22][23][24], and the geometric mean APV C min for unboosted FPV (0.351 mg/ mL) and FPV/RTV (2.88 mg/mL) during TDF coadministration remained 2.4-and 19.7-fold higher than the documented protein binding-adjusted 50% inhibitory concentration (IC 50 ) for wild-type HIV isolates (0.146 mg/mL), respectively [25].…”

Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

“…Profiles of TFV in plasma and TFV/TFV-DP in PBMCs. Figure 3 displays for fetuses and neonates the observed and predicted TFV concentrations in plasma, TFV concentrations in PBMCs, and TFV-DP concentrations in PBMCs as a function of time in our study and the plasma TFV and TFV-DP concentrations reported in previous studies of adults (15,17,19,20). Fetal and neonatal plasma TFV and IC TFV-DP concentrations were compared to adult values measured in the same laboratory with the same method of dosage (20,21).…”