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

Cressey, Tim R.; Urien, Saı̈k; Capparelli, Edmund V.; Best, Brookie M.; Buranabanjasatean, Sudanee; Limtrakul, Aram; Rawangban, Boonsong; Sabsanong, Prapan; Tréluyer, Jean Marc; Jourdain, Gonzague; Stek, Alice; Lallemant, Marc; Mirochnick, Mark

doi:10.1093/jac/dku367

Cited by 11 publications

(14 citation statements)

References 27 publications

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“…The factors that influence the inter-patient variability in pharmacokinetic exposure to orally administered drugs have been well studied and are for the most part drug-specific, involving interrelated factors such as pharmacogenetics [148, 149], body weight [150, 151], gender [152, 153], and drug-drug interactions [154]. As new LA agents become available it will be necessary to determine whether such factors play an equal role in pharmacokinetic variability, or whether other as yet understudied mechanisms contribute or even predominate.…”

Section: Gaps In Knowledge Regarding the Pharmacology Of Solid Drumentioning

confidence: 99%

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Owen

Rannard

2016

Advanced Drug Delivery Reviews

117

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Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

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Section: Gaps In Knowledge Regarding the Pharmacology Of Solid Drumentioning

confidence: 99%

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Owen

Rannard

2016

Advanced Drug Delivery Reviews

117

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“…Efavirenz is primarily metabolized by the hepatic cytochrome 2B6 enzyme (CYP2B6) [9] and temporal changes in hepatic drug-metabolizing enzyme activities occur during pregnancy [10]. Several antiretroviral drugs metabolized via the hepatic cytochrome P450 enzymes have reduced exposure during pregnancy, particularly during the third trimester [11,12]. Data are scarce on the impact of pregnancy on efavirenz pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Efavirenz Pharmacokinetics during Pregnancy and Infant Washout

et al. 2018

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Background: Limited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout. Methods: HIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-hour pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6–12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 mcg.hr/mL) and a trough concentration (C24 hour) of 1 mcg/mL. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe). Results: Among 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7–43.5) years, weight 74 (50–132) kg, and gestational age 33.4 (28.4–37.9 weeks). Efavirenz AUC during the third trimester (60 ug*h/mL) was similar to that reported in non-pregnant adults (58 ug*h/mL). Exposure in the second trimester was lower, but within the 0.80–1.25 range. C24 concentrations during pregnancy, were lower compared to historical controls on 600mg EFV, however, they were similar to the C24 concentrations after equally potent dose of 400mg EFV. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36–0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 hours (40.6– 129). HIV RNA viral load at delivery were <400 and <50 copies/mL for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8 /41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target. Conclusions Efavirenz exposure was similar during pregnancy compared to postpartum, C24 was in line with C24 after 400mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants.

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“…Lopinavir was measured by the Pediatric Pharmacology Laboratory at University of California, San Diego (UCSD) and AMS-PHPT Pharmacology Laboratory at the Faculty of Associated Medical Sciences, Chiang Mai University, Thailand. Both laboratories utilized previously described, validated, reversed-phase multiplex high performance liquid chromatography (HPLC) methods [4] [5]. Both laboratories participated in the DAIDS Clinical Pharmacology QA/QC program which includes proficiency testing for lopinavir in tests samples twice a year.…”

Section: Methodsmentioning

confidence: 99%

A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

Pinto

Capparelli²,

Warshaw

et al. 2018

Pediatric Infectious Disease Journal

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

Abstract: 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.

Cited by 11 publications

References 27 publications

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Efavirenz Pharmacokinetics during Pregnancy and Infant Washout

A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

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