Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy

Abstract

Objectives: To assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy.

Patients and methods: Lopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (>1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy.

Results: The median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and volume of distribution (V/F). Population estimates of lopinavir CL/F and V/F were 6.21 L/h/70 kg and 52.6 L/70 kg, respectively. Based on simulations, the highest risk of subtherapeutic trough concentrations was for women weighing >100 kg using the standard dose (∼ 7%), while the risk was <2% with the 600/150 mg dose for women weighing 40-130 kg. After a missed dose, 61% of women have lopinavir concentrations below target prior to the next dose with the standard dose compared with 42% with the increased dose.

Conclusions: Standard dosing provides adequate lopinavir trough concentrations for the majority of pregnant women but increased doses may be preferable for women weighing >100 kg and with a history of lopinavir/ritonavir use and/or adherence issues.

Keywords: HIV; Thailand; USA; pharmacokinetics.

© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Visual predictive check for lopinavir population pharmacokinetic models following (a) 400/100 mg of lopinavir/ritonavir twice daily and (b) 600/150 mg of lopinavir/ritonavir twice daily. Lines represent the predicted population 5%, 50% and 95% percentiles and shaded areas are the 90% CIs. Observed concentrations from the patients are superimposed.

Figure 2.

Percentage of women failing to achieve lopinavir trough >1.0 mg/L with 400/100 and 600/150 mg of lopinavir/ritonavir twice daily, for pregnant women with body weights between 40 and 130 kg based on 500 Monte Carlo simulations. LPV/r, lopinavir/ritonavir.

Figure 3.

Simulated lopinavir concentration–time curves following a missed dose with (a) 400/100 mg of lopinavir/ritonavir twice daily and (b) 600/150 mg of lopinavir/ritonavir twice daily. Lines represent the 5%, 50% and 95% percentiles and shaded areas are the 90% CIs. The broken line represents the target lopinavir Ctrough of 1.0 mg/L for treatment-naive patients. LPV/r, lopinavir/ritonavir; bd, twice daily.