Free and Total Plasma Levels of Lopinavir during Pregnancy, at Delivery and Postpartum: Implications for Dosage Adjustments in Pregnant Women

Fayet-Mello, Aurélie; Buclin, Thierry; Guignard, Nicole; Cruchon, Sandra; Cavassini, Matthias; Grawe, Claudia; Gremlich, Erika; Popp, Karoline Aebi; Schmid, Flavia; Eap, Chin B.; Telenti, Amalio; Biollaz, J.; Décosterd, Laurent A.; Tejada, Begoña Martínez de

doi:10.3851/imp2328

Cited by 32 publications

(35 citation statements)

References 39 publications

(76 reference statements)

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“…The unbound fraction (F u ) was estimated by using the trough concentration; in pregnant women, the median F u was 1.5%. This value is comparable to those previously described (0.84 to 2%) (12,14,23,34). Moreover, bootstrap, VPC, and NPDE procedures allowed a good evaluation of these two models.…”

Section: Discussionsupporting

confidence: 75%

“…Placental transfer was estimated based on the exposure ratio between fetal and maternal LPV/r AUCs for 12 h. The placental transfer was estimated to be 11.6% (1.2% to 48.9%). This value is slightly lower than those suggested for the fetal-to-maternal concentration ratio at delivery (14 to 20%) (8,(19)(20)(21)(22)(23).…”

Section: Resultscontrasting

confidence: 42%

“…These values for plasma protein concentrations come from nonpublished data of our lab and reported values (23,34).…”

Section: Population Pharmacokinetic Analysis (I) Model Developmentmentioning

confidence: 99%

“…The total LPV concentrations were linked to the unbound concentrations by relationships integrating the HSA and the AAG concentrations. Alternative relationships were examined by linear and nonlinear protein binding regression in both cases (for example, saturable binding regression for HSA and linear binding regression for AAG [23]). …”

Section: Population Pharmacokinetic Analysis (I) Model Developmentmentioning

confidence: 99%

“…The LPV placental transfer is low and variable at 20% (coefficient of variation [CV], ϳ65%) (8,(19)(20)(21)(22)(23), but this transfer has only been reported as a ratio of concentrations, whatever the delay between drug administration and delivery. The LPV placental transfer variability can be explained by the differences of delays and may also be explained by the genetic polymorphisms of the placental transporters.…”

mentioning

confidence: 99%

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

Fauchet

Tréluyer

Illamola

et al. 2015

Antimicrob Agents Chemother

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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...

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Section: Discussionsupporting

confidence: 75%

Section: Resultscontrasting

confidence: 42%

“…These values for plasma protein concentrations come from nonpublished data of our lab and reported values (23,34).…”

Section: Population Pharmacokinetic Analysis (I) Model Developmentmentioning

confidence: 99%

Section: Population Pharmacokinetic Analysis (I) Model Developmentmentioning

confidence: 99%

mentioning

confidence: 99%

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

Fauchet

Tréluyer

Illamola

et al. 2015

Antimicrob Agents Chemother

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Chromatographic methods in HIV medicine: Application to therapeutic drug monitoring

Archibald

Murrell

Brown

2018

Biomedical Chromatography

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HIV antiretroviral therapy spans several different drug classes, meant to combat various aspects of viral infection and replication. Many authors have argued the benefits of therapeutic drug monitoring (TDM) for the HIV patient including compliance assurance and assessment of appropriate drug concentrations; however, the array of drug chemistries and combinations makes TDM an arduous task. HPLC-UV and LC-MS/MS are both frequent instruments for the quantification of HIV drugs in biological matrices with investigators striving to balance sensitivity and affordability. Plasma, the dominant matrix for these analyses, is prepared using protein precipitation, liquidliquid extraction or solid-phase extraction depending on the specific complement of analytes.

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Pharmacokinetics of Antiretroviral Agents in Pregnant Individuals Living With HIV: Current Status and Considerations for Study Design and Interpretation

Choi

Yang

Belew

et al. 2023

The Journal of Clinical Pharma

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Determining the appropriate dosing regimens of antiretroviral (ARV) drugs for pregnant individuals living with HIV‐1 infection is critical to maximize maternal health and prevent perinatal HIV transmission. Throughout pregnancy, pharmacokinetics (PK) of ARVs can be significantly altered due to physiological, anatomic, and metabolic changes. As such, conducting PK studies of ARVs during pregnancy is crucial to optimize dosing regimens. In this article, we summarize available data, key issues, challenges, and considerations in interpreting results of ARV PK studies in pregnant individuals. Discussion topics include the choice of the reference population (postpartum vs historical control), pregnancy trimester‐dependent changes in ARV PK, effects of pregnancy on once‐ versus twice‐daily dosing, factors to consider for ARVs that are administered with a PK booster such as ritonavir and cobicistat, and considerations when evaluating the effects of pregnancy on unbound ARV concentrations. Common approaches for the translation of the results into clinical recommendations and rationales and considerations when making clinical recommendations are summarized. Currently, limited PK data in pregnancy are available with long‐acting ARVs. Collection of PK data to characterize the PK profile of long‐acting ARVs is an important goal shared by many stakeholders.

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Free and Total Plasma Levels of Lopinavir during Pregnancy, at Delivery and Postpartum: Implications for Dosage Adjustments in Pregnant Women

Cited by 32 publications

References 39 publications

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

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

Chromatographic methods in HIV medicine: Application to therapeutic drug monitoring

Pharmacokinetics of Antiretroviral Agents in Pregnant Individuals Living With HIV: Current Status and Considerations for Study Design and Interpretation

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