Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

Abstract

The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy. N ew recommendations were published by the World Health Organization (WHO) in 2013 for use of antiretroviral drugs for treating and preventing HIV infection (1). These recommendations suggested simplification and harmonization of the firstline therapy in order to improve health outcomes and facilitate adherence and drug procurement (1). A new combination regimen has been suggested for all HIV-infected adults, including pregnant and breastfeeding women. Two nucleoside reverse transcriptase inhibitors (NRTIs) and one nonnucleoside reverse transcriptase inhibitor are recommended as a first-line regimen to treat infected pregnant women or to prevent mother-to-child transmission (MTCT). However, the use of NRTIs during pregnancy has been recently debated. Indeed, NRTIs cross the placenta with an affinity for both mitochondrial and nuclear human DNA (2, 3). The use of NRTIs in large cohorts of neonates and children has been associated with toxicities (including mitochondrial dysfunction and neurological disease) (4, 5). Moreover, genotoxic biomarkers were identified in neonates exposed to zidovudine (ZDV) alone or in combination with lamivudine (3TC) (6, 7). The long-term toxicities of NRTIs remain unknown, but they raise concern about use of these drugs during pregnancy.Considering the possible NRTI toxicities during pregnancy, the ANRS 135 PRIMEVA study compared a triple-therapy regimen containing NRTIs versus LPV monotherapy. The study also compared the effi...

Neglecting Plasma Protein Binding in COVID‐19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure

“…11 Such a link between the inflammatory state (increased AAG) and changes in T-lopinavir was previously described in pregnant women. 12,13 Yet, studies published so far describing the pharmacokinetics of lopinavir in patients with COVID-19 have overlooked the importance of changes in plasma protein binding, which could lead to a wrong interpretation of lopinavir overexposure. Although international guidelines have recently recommended against using lopinavir/ritonavir (https://www.covid 19tre atmen tguid elines.nih.gov/antiv iral-thera py/) to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a drug total exposure when changes in protein binding are not taken into consideration.…”

“…In patients with COVID‐19, increased T‐lopinavir is the result of an increased AAG‐bound lopinavir plasma concentration whereas U‐lopinavir remains constant, and insufficient to reduce the SARS‐CoV‐2 viral load 11 . Such a link between the inflammatory state (increased AAG) and changes in T‐lopinavir was previously described in pregnant women 12,13 . Yet, studies published so far describing the pharmacokinetics of lopinavir in patients with COVID‐19 have overlooked the importance of changes in plasma protein binding, which could lead to a wrong interpretation of lopinavir overexposure.…”

Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model

“…The moderate molecular weight and lipophilic nature of dolutegravir (molecular weight of 419.129 g/mol, water solubility 95 mg/L at 25 °C and Octanol/Water Partition Coefficient of 2.2) [30], favor its placental transfer. On the other hand, dolutegravir is 99% bound to plasma proteins, mainly albumin, which is important because only the unbound form of the drug can equilibrate across the placental barrier [31]. Our group showed, for another highly protein-bound antiretroviral drug, the HIV protease inhibitor lopinavir, [32] that the FTR in the ex vivo placental perfusion model decreased as albumin concentrations in the perfusate were increased.…”

Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator

“…It was assumed that unbound fraction of GLP-26 in plasma is related to antiviral efficacy [ 16 ] The unbound fraction of GLP-26 was measured in cynomolgus monkey (1 donor) and human (6 donors pooled) plasma and in 2% bovine serum (FBS), utilizing a Centrifree Ultrafiltration Device with an Ultracel PL membrane, following the instructions included by the manufacturer (Millipore Sigma, St. Louis, MO, USA). For comparison, lopinavir (positive control, reported to be ~98 to 99% bound in human plasma) or emtricitabine (negative control, reported to be <4% bound) were analyzed in spiked human plasma in the same experimental run [ 17 , 18 ]. Plasma and 2% FBS samples were spiked with 10 µM of a test compound, placed in the tube above the membrane and the tubes were centrifuged.…”