Antiretroviral unbound concentration during pregnancy: piece of interest in the puzzle?

Metsu, David; Toutain, Pierre‐Louis; Chatelut, Étienne; Delobel, Pierre; Gandia, Peggy

doi:10.1093/jac/dkx176

Cited by 10 publications

(6 citation statements)

References 19 publications

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“…As mentioned in the opening statement, an important and well‐described pharmacological process that changes during pregnancy is drug protein binding . The main binding proteins in plasma are albumin and α 1 ‐acid glycoprotein (AAG) .…”

Section: Changes In Total and Free Antiretroviral Concentration Durinmentioning

confidence: 99%

“…This leads us to the following rule of thumb: if we want to identify pregnancy‐induced changes (or for any other condition in which protein concentrations are substantially altered) in the pharmacologically active C free , for highly protein bound drugs we need to measure C free . This is by no means a new insight . Still, for some clinical pharmacokinetic studies with highly bound drugs there is room for improvement as in general only C tot is measured.…”

Section: Changes In Total and Free Antiretroviral Concentration Durinmentioning

confidence: 99%

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Free dug concentrations in pregnancy: Bound to measure unbound?

Schalkwijk

Greupink

Burger³

2017

Brit J Clinical Pharma

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Section: Changes In Total and Free Antiretroviral Concentration Durinmentioning

confidence: 99%

Section: Changes In Total and Free Antiretroviral Concentration Durinmentioning

confidence: 99%

Free dug concentrations in pregnancy: Bound to measure unbound?

Schalkwijk

Greupink

Burger³

2017

Brit J Clinical Pharma

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“…RAL highly binds to human serum albumin (HSA) (83%) (22,41). Thus, the decrease in plasma protein concentration reported during pregnancy could lead to an increase in the unbound fraction of RAL (24,25).…”

mentioning

confidence: 99%

Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial

Zheng

Hirt

Delmas

et al. 2020

Antimicrob Agents Chemother

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OBJECTIVES: A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. METHOD: RalFe ANRS160 study was a non-randomized, open label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing raltegravir 400 mg twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. RESULT: A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one compartment model with a transit compartment with first order absorption, evolving either to bound raltegravir (by a linear binding to albumin), or metabolism to RAL-glucuronide or to a first order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound AUC0-12h significantly decreased by 37 and 27% during pregnancy. Median total Ctrough decreased significantly in the evening (28%), however median total Ctrough in the morning, unbound Ctrough in the morning and unbound Ctrough in the evening showed a non-significant decrease, respectively 16%, 1% and 15% during pregnancy compared to the postpartum period. CONCLUSION: This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound Ctrough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered as clinically relevant.

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“…While the relationship between dose and total exposure is nonlinear, that between dose and unbound exposure may be linear [23], which brings us to another limitation of our study: only total concentrations were measured. With DRV being highly protein bound, it has been argued that unbound concentrations could be a useful biomarker for therapeutic drug monitoring (TDM) [59]. If DRV is assumed to have a low extraction ratio, displacement of its binding to AAG could affect the total concentration without influencing the unbound concentration, rendering the interpretation of TDM more delicate.…”

Section: Discussionmentioning

confidence: 99%

Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations

et al. 2020

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Background and objectives Protease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naïve patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations. Methods Sparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated. Results Our model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure were CYP3A5*3 and SLCO3A1 rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC 50 in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients. Conclusions These results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models. Clinical Trial Registration ClinicalTrials.gov identifier: NCT03101644, date of registration: 5 April, 2017. Electronic supplementary material The online version of this article (10.1007/s40262-020-00920-z) contains supplementary material, which is available to authorized users.

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Antiretroviral unbound concentration during pregnancy: piece of interest in the puzzle?

Cited by 10 publications

References 19 publications

Free dug concentrations in pregnancy: Bound to measure unbound?

Free dug concentrations in pregnancy: Bound to measure unbound?

Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial

Exploration of Reduced Doses and Short-Cycle Therapy for Darunavir/Cobicistat in Patients with HIV Using Population Pharmacokinetic Modeling and Simulations

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