Pharmacokinetics and 48-week safety and efficacy of generic ritonavir tablet-boosted atazanavir in HIV-1-infected Thai adults.

BACKGROUND: Ritonavir (RTV) tablets were not available in Thailand until they were manufactured by the Government Pharmaceutical Organization of Thailand. We assessed pharmacokinetics (PK), safety and efficacy of generic RTV-boosted atazanavir (ATV) in virologically suppressed HIV-1-infected Thai adults. METHODS: Virologically suppressed HIV-1-infected Thai adults who currently use ATV (either 200 or 300 mg) with Norvir® soft gel capsule (SGC) 100-mg-based regimen were enrolled into this prospective, 48-week single-arm study. Participants switched from Norvir® SGC to generic RTV. Plasma trough concentration (Ctrough) was assessed at baseline before switching to generic RTV and week 24 in all participants, with the target ATV Ctrough of 0.15 mg/l. Plasma HIV-1 RNA and other laboratory safety parameters were assessed until week 48. RESULTS: Of 100 participants (51% male) enrolled, 50% was using ATV 200 mg and 50% was using 300 mg at the time RTV SGC were changed into generic tablets. All participants used two nucleoside reverse transcriptase inhibitors (NRTIs) as backbone. There were no significant changes in mean (sd) Ctrough of RTV (0.20 [0.33] versus 0.23 [0.39]; P=0.21) and ATV (0.83 [0.93] versus 0.88 [0.95]; P=0.62) between baseline and week 24. From entry to week 48, median alanine aminotransferase significantly increased from 25 to 30 IU/l (P=0.001) and total bilirubin significantly decreased from 1.7 to 1.3 (P=0.04). One study drug related grade 3 adverse event was reported. All but one participant maintained plasma HIV-1 RNA <50 copies/ml after 48 weeks. CONCLUSIONS: Generic RTV-boosted ATV showed adequate levels, good tolerability and great efficacy after 48 weeks.

Population pharmacokinetics and dose optimisation of ritonavir-boosted atazanavir in Thai HIV-infected patients.

There is evidence that Thai patients receiving standard doses of ritonavir (RTV)-boosted atazanavir (ATV/r) have high exposure to atazanavir (ATV) leading to a higher risk of toxicity. A lower dose of ATV/r may provide adequate exposure in this population. However, pharmacokinetic data on ATV/r in Thai patients required for dose adjustment are limited. This study aimed to develop a population pharmacokinetic model of ATV/r and to determine the influence of patient characteristics on ATV pharmacokinetics. Monte Carlo simulations were performed to estimate the proportion of patients achieving target ATV trough concentration (Ctrough) with the standard ATV/r dose of 300/100 mg and a low dose of 200/100 mg once daily (OD). A total of 127 Thai HIV-infected patients were included in this study. One random blood sample was collected to determine ATV and RTV concentrations at each clinic visit from 100 patients. Intensive data from 27 patients enrolled in previous studies were also included. Data were analysed using the non-linear mixed-effects modelling approach. A one-compartment model with first-order absorption and elimination and absorption lag time best described the data. The population mean clearance of ATV/r was 4.93 L/h in female patients and was 28.7% higher in male patients. Simulation results showed a higher proportion of patients achieving ATV Ctrough within the target range with ATV/r 200/100 mg compared with 300/100 mg. The 200/100 mg OD dose of ATV/r provides adequate ATV exposure in Thai HIV-infected patients. Therefore, a lower dose of ATV/r should be considered for Thai and Asian populations.

Prediction of pH dependent absorption using in vitro, in silico, and in vivo rat models: Early liability assessment during lead optimization.

Weakly basic compounds which have pH dependent solubility are liable to exhibit pH dependent absorption. In some cases, a subtle change in gastric pH can significantly modulate the plasma concentration of the drug and can lead to sub-therapeutic exposure of the drug. Evaluating the risk of pH dependent absorption and potential drug-drug interaction with pH modulators are important aspects of drug discovery and development. In order to assess the risk around the extent of decrease in the systemic exposure of drugs co-administered with pH modulators in the clinic, a pH effect study is carried out, typically in higher species, mostly dog. The major limitation of a higher species pH effect study is the resource and material requirement to assess this risk. Hence, these studies are mostly restricted to promising or advanced leads. In our current work, we have used in vitro aqueous solubility, in silico simulations using GastroPlus™ and an in vivo rat pH effect model to provide a qualitative assessment of the pH dependent absorption liability. Here, we evaluate ketoconazole and atazanavir with different pH dependent solubility profiles and based on in vitro, in silico and in vivo results, a different extent of gastric pH effect on absorption is predicted. The prediction is in alignment with higher species and human pH effect study results. This in vitro, in silico and in vivo (IVISIV) correlation is then extended to assess pH absorption mitigation strategy. The IVISIV predicts pH dependent absorption for BMS-582949 whereas its solubility enhancing prodrug, BMS-751324 is predicted to mitigate this liability. Overall, the material requirement for this assessment is substantially low which makes this approach more practical to screen multiple compounds during lead optimization.