Population Pharmacokinetics of Ainuovirine and Exposure–Response Analysis in Human Immunodeficiency Virus-Infected Individuals
The emergence of antiretroviral therapy (ART) has transformed HIV from a fatal disease into a chronic condition, significantly reducing morbidity and mortality. ART typically involves a combination of three or more drugs targeting different stages of the HIV life cycle. However, the emergence of drug resistance, poor treatment compliance, and side effects of existing drugs like efavirenz (EFV) have necessitated the development of new antiretroviral agents. Ainuovirine (ANV), a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown promise in this regard. This study aimed to evaluate the population pharmacokinetics (PopPK) and exposure–response relationship of ANV in people living with HIV (PLWH).
The study pooled plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV to develop the PopPK model. The phase 1 trial involved 28 treatment-naïve PLWH who received ANV at doses of 75, 150, or 300 mg once daily for 10 days. The phase 3 trial included 309 treatment-naïve PLWH who were randomized to receive either an ANV-based regimen or an EFV-based regimen for 48 weeks. The PopPK model was developed using nonlinear mixed effects modeling, and the exposure–response analysis evaluated the relationship between ANV exposure and virologic and safety outcomes.
ANV exhibited nonlinear pharmacokinetics, with dose-normalized area under the curve (AUC) and maximum plasma concentration (Cmax) decreasing as the dose increased. The PopPK model identified a two-compartment model with first-order elimination as the best fit for ANV pharmacokinetics. The clearance of ANV increased after multiple doses, likely due to the auto-induction of cytochrome P450 3A4 (CYP3A4). The final model estimated the population typical value for clearance adjusted for bioavailability (CL/F) to be 6.46 L/h, with a 147% increase in steady-state CL/F compared to the first dose. The elimination half-life at steady state was 24.5 hours.
Covariate analysis revealed no significant covariates affecting the pharmacokinetic parameters of ANV. Age, gender, weight, body mass index (BMI), and other factors such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine clearance (CrCL) did not significantly influence ANV pharmacokinetics. This suggests that no dose adjustment is necessary for the studied factors.
The exposure–response analysis revealed a positive but not statistically significant relationship between ANV exposure and virologic response. The proportion of patients achieving HIV-RNA levels below 50 copies/mL at 48 weeks slightly increased with higher exposure, but the effect plateaued at higher exposure levels. Logistic regression models indicated no significant improvement in model fit when comparing the relationship between exposure and virologic response to a constant probability model.
In contrast, the incidence of adverse events increased with higher ANV exposure. Logistic regression models showed a significant positive correlation between ANV exposure and the incidence of adverse drug reactions (ADRs). The probability of ADRs increased with higher steady-state trough concentrations (Ctrough) and area under the steady-state curve (AUCtau). This highlights the importance of selecting the optimal dose to minimize adverse reactions while maintaining efficacy.
The study concluded that ANV 150 mg once daily is the recommended dose for PLWH, as it provides a robust antiviral response without requiring dose adjustments for the studied factors. However, the increasing trend in adverse reactions with higher exposure suggests that careful dose optimization may be necessary in clinical practice.
The PopPK model developed in this study provides valuable insights into the pharmacokinetics of ANV and its exposure–response relationship. The model was internally validated using a non-parametric bootstrap method, which confirmed the accuracy and reliability of the parameter estimates. The prediction-corrected visual predictive check (pcVPC) also demonstrated good consistency between observed and predicted values.
One limitation of the study is the limited age range and low proportion of female participants, which may have reduced the ability to identify significant covariates. Additionally, the data used to build the PopPK model came from a single institution, which could introduce bias. Future studies with a more diverse population and broader sampling are needed to further validate these findings.
In summary, this study provides a comprehensive evaluation of the pharmacokinetics and exposure–response relationship of ANV in PLWH. The findings support the use of ANV 150 mg once daily as an effective and well-tolerated treatment option for HIV-1 infection. The study also highlights the importance of monitoring and managing adverse reactions associated with higher ANV exposure.
doi.org/10.1097/CM9.0000000000002917
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