Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling

Abstract

Background: Darunavir 800 mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available.

Objectives: To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women.

Patients and methods: A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC0-τ and Ctrough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure.

Results: Simulations predicted that total darunavir exposure (AUC0-τ) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC0-τ was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%).

Conclusions: The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Darunavir protein binding. Based on unpublished data from the registration package, bound and unbound darunavir plasma concentrations were plotted. Each dot represents the mean of two values. Using non-linear least-squares estimation based on Supplementary data S1, Equation (1), the Bmax and Kd (95% CI) were 18 (16–20) mg/L and 1.16 (0.83–1.7) mg/L, respectively. Dashed and dotted-dashed lines represent the typical binding kinetics in non-pregnant (i.e. post-partum) and pregnant (i.e. third trimester) women, respectively, based on the parameters listed in Table 2.

Figure 2.

Schematic of the final darunavir/ritonavir model. Left: final structural model for ritonavir. Right: final structural model for darunavir. A fraction of the ritonavir dose (F) enters the central compartment through sequential zero-order absorption (D1, duration of zero-order process) and first-order absorption (ka, absorption rate constant). Ritonavir is cleared from the central compartment. Darunavir is absorbed through one transit compartment into the liver compartment, based on two identical first-order rate constants (ktr). For the first pass through the liver a fraction of the darunavir amount is extracted (Eh) and cleared; the fraction remaining (1 − Eh) reaches the systemic circulation and becomes available for redistribution into the peripheral compartment. Darunavir recirculates from the central compartment to the liver with a flow equivalent to liver plasma flow (Qh) and at each pass the liver extracts a further fraction (Eh). Pregnancy impacts ritonavir bioavailability and darunavir Bmax. Total darunavir concentrations in the central compartment impact fu. Total ritonavir concentrations in the central compartment inhibit CLint. Relations indicated with dashed lines were estimated. Relations indicated with solid lines were fixed in the final darunavir/ritonavir model. DRV, darunavir; RTV, ritonavir.

Figure 3.

Exploration of darunavir dosing. Simulated typical daily darunavir exposure (AUC0–12) during the third trimester of pregnancy (at 38 weeks of gestation) and post-partum versus darunavir dose for q12h dosing; darunavir always co-administered with standard ritonavir (100 mg).