Darunavir Pharmacokinetics With an Increased Dose During Pregnancy

Ahizechukwu C. Eke, MD, MPH; Alice M. Stek, MD; Jiajia Wang, MS; Regis Kreitchmann, MD, PhD; David E. Shapiro, PhD; Elizabeth Smith, MD; Nahida Chakhtoura, MD; Edmund V. Capparelli, PharmD; Mark Mirochnick, MD; Brookie M. Best, PharmD, MAS

Disclosures

J Acquir Immune Defic Syndr. 2020;83(4):373-380. 

In This Article

Abstract and Introduction

Abstract

Background: This study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum.

Methods: Darunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2–3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography. Target darunavir area under the concentration time curve (AUC) was >70% (43.6 μg × h/mL) of median AUC (62.3 μg × h/mL) in nonpregnant adults on twice daily darunavir-ritonavir 600/100 mg.

Results: Twenty-four women were included in the analysis. Darunavir AUC0–12 was lower with the increased dose during the second {[geometric mean ratio (GMR) of 0.62 (IQR 0.44–0.88); P = 0.055]} and third trimesters [GMR 0.64 (IQR 0.55–0.73); P = <0.001] compared with postpartum. Darunavir apparent clearance was higher during the second [GMR 1.77 (IQR 1.24–2.51); P = 0.039] and third trimesters [GMR 2.01 (IQR 1.17–2.35); P = <0.001] compared with postpartum. Similarly, ritonavir AUC0–12 was lower during the third trimester [GMR 0.65 (IQR 0.52–0.82); P = 0.007] compared with postpartum, whereas its apparent clearance was higher during the third trimester [GMR 1.53 (IQR 1.22–1.92); P = 0.008] compared with postpartum. No major drug-related safety concerns were noted.

Conclusions: Increasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared with 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.

Introduction

Darunavir (DRV), in combination with low-dose ritonavir, is one of the 2 protease inhibitors (PIs) currently recommended by the US Perinatal Guidelines Panel for use in pregnant women living with HIV for treatment of HIV infection and for prevention of perinatal transmission.[1] In most countries, darunavir is available as 600 and 800 mg tablets, and dosed as darunavir/ritonavir (DRV/RTV) 800 mg/100 mg daily for darunavir naive patients and 600 mg/100 mg twice daily for treatment of antiretroviral (ARV) experienced patients. Because of physiological changes that occur during pregnancy, there is decreased exposure to many PIs during the third trimester of pregnancy.[2,3]

The clinical relevance of these changes during pregnancy were described in prior PK studies of DRV/RTV during pregnancy and postpartum.[4–7] In PK studies of 600 mg/100 mg DRV/RTV twice daily and 800 mg/100 mg DRV/RTV, darunavir and ritonavir exposures (area under the concentration time curve and plasma trough concentrations) were lower during the third trimester of pregnancy compared with postpartum.[4–7] For pregnant women living with HIV, these lower ARV drug exposures during pregnancy can increase the risk of maternal viremia, and, in turn, increase the potential for drug resistance and perinatal transmission.[8] Although plasma concentrations of RTV-boosted DRV were lower during pregnancy compared with postpartum in these prior studies, the reduced DRV concentrations were still above the exposures needed for viral suppression.

Examining known pharmacokinetic-pharmacodynamic (PKPD) relationships of darunavir (AUC, viral response and protein-adjusted IC50/IC90) in the context of lower exposures and what a clinically relevant decrease means in relation to these targets is critical during pregnancy. Three darunavir/ritonavir randomized clinical trials-POWER I,[9] POWER II,[10] and POWER III[11] demonstrated a dose-response relationship between darunavir plasma trough concentrations (Cmin) and HIV antiviral response.[12,13] However, this PKPD relationship between Cmin and viral response were not observed in 2 other darunavir randomized clinical trials-ODIN[14] and ARTEMIS.[15,16] Hence, darunavir exposure-response data from these 5 trials were not sufficient to recommend a minimum trough concentration.[17] Therefore, darunavir Cmin may not be the most appropriate PK parameter to evaluate DRV/RTV antiviral response. The established darunavir EC50 for wild-type virus and resistant-type virus are 0.055 μg/mL[17,18] and 0.55 μg/mL respectively,[19] whereas darunavir EC90 for wide type virus is 0.2. These parameters are frequently used for monitoring response of darunavir in both treatment-naive and treatment-experienced patients in pregnant and nonpregnant adults.

Because of low darunavir/ritonavir concentrations with 800 mg once-daily dosing of darunavir in these studies, only the 600 mg twice-daily dosing is currently recommended by the US Perinatal Guidelines Panel for use in pregnancy.[1] The objective of the current study was to evaluate the hypothesis that an increased dose darunavir (800/100 twice daily) during pregnancy would increase darunavir plasma exposure to levels similar to those seen in nonpregnant women.

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