Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women*

Colbers, Angela; Moltó, José; Ivanovic, Jelena; Kabeya, Kabamba; Hawkins, David; Gingelmaier, Andrea; Taylor, Graham P.; Weizsäcker, Katharina; Sadiq, S Tariq; Ende, Marchina van der; Giaquinto, Carlo; Burger, David M.; Ven, A.J.A.M. van der; Warris, Adilia; Nellen, Jeannine; Lyons, F; Lambert, John S.; Haberl, Annette; Fäetkenheuer, Gerd; Wyen, Christoph; Rockstroh, Jürgen K.; Schwarze-Zander, C; Gilleece, Yvonne; Wood, Chris

doi:10.1093/jac/dku400

Cited by 41 publications

(54 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of antiretrovirals, all studies had showed decreased drug exposure in pregnancy due to PK changes. While most of these studies reported adequate viral suppression and no mother-to-child HIV transmission [132,135,138], one study reported an increased viral load during pregnancy, with a few cases of neonatal transmission of the virus [150]. Conflicting clinical results were also reported for antimalarial drugs: while some studies reported equal parasite clearance time or no increase in treatment failure in spite of decreased exposure [182], others demonstrated a positive correlation between the decreased exposure and poor clinical outcome, reporting an increase in treatment failure or a decrease in post-treatment prophylactic effect [181,195].…”

Section: Discussionmentioning

confidence: 99%

“…This collection of PK data could prove to be a decision support base for future attempts to tailor medication prescription for pregnant women to achieve target serum concentrations; however, one must take into account that many studies often report undiminished drug efficacy despite the aforementioned pregnancy-associated PK changes [132,135,138,145,146,163,172,177]. …”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

et al. 2016

View full text Add to dashboard Cite

BackgroundWomen are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy.Methods and FindingsSystematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown.ConclusionThis systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

et al. 2016

View full text Add to dashboard Cite

show abstract

“…These results are consistent with previously published case reports and smaller series of patients. 10-16 Zorrilla, et al, reported a decrease of 17-24% in darunavir AUC in 14 women dosed twice daily in the second and third trimesters. 15 Colbers, et al reported a mean decrease in darunavir AUC of 34% in 6 women with twice daily dosing and 22% in18 women with once daily dosing in the third trimester.…”

Section: Discussionmentioning

confidence: 99%

“…Published data describing darunavir pharmacokinetics during pregnancy are limited. 10-16 The primary objectives of this study were to describe darunavir pharmacokinetics in HIV-infected pregnant women receiving once and twice daily dosing and to determine if standard doses of darunavir produce equivalent drug exposure during pregnancy to that in nonpregnant adults. We also sought to evaluate transplacental passage of darunavir by comparing concentrations in cord blood and maternal blood at delivery.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Once Versus Twice Daily Darunavir in Pregnant HIV-Infected Women

Stek

Best

Wang

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

Objective To describe darunavir pharmacokinetics with once and twice daily dosing during pregnancy and postpartum in HIV-infected women. Design Women were enrolled in International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1026s, a prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included separate cohorts receiving darunavir/ritonavir dosed at either 800 mg/100 mg once daily or 600 mg/100 mg twice daily. Methods Intensive steady-state 12 or 24 hour pharmacokinetic profiles were performed during the second trimester, third trimester and postpartum. Darunavir was measured using high performance liquid chromatography (detection limit: 0.09 μg/mL). Results Pharmacokinetic data were available for 64 women (30 once daily and 34 twice daily dosing). Median darunavir area under the concentration-time curve (AUC) and maximum concentration (Cmax) were significantly reduced during pregnancy with both dosing regimens compared to postpartum, while the last measurable concentration (Clast) was also reduced during pregnancy with once daily darunavir. Darunavir AUC with once daily dosing was reduced by 38% during the second trimester and by 39% during the third trimester. With twice daily dosing, darunavir AUC was reduced by 26% in both trimesters. The median (range) ratio of cord blood/maternal delivery darunavir concentration in 32 paired samples was 0.18 (range: 0 – 0.82). Conclusion Darunavir exposure is reduced by pregnancy. In order to achieve darunavir plasma concentrations during pregnancy equivalent to those seen in non-pregnant adults, an increased twice daily dose may be necessary. This may be especially important for treatment-experienced women who may have developed antiretroviral resistance mutations.

show abstract

“…As a result of pregnancy induced CYP450 enzyme induction, the standard adult dose of ritonavir (RTV)-boosted DRV (DRV/r) of 800mg/100mg daily results in inadequate DRV exposure during the third trimester [21, 32*, 33*]. A twice daily dose of DRV/r (600mg/100mg) is recommended instead, and although this dose also results in reduced exposure during the third trimester compared to post-partum, it is thought to be adequate [34].…”

Section: Universal Art Regimens: Considerations For Pregnant and Breamentioning

confidence: 99%

Toward a universal antiretroviral regimen

Slogrove

Clayden²,

Abrams

2017

Current Opinion in HIV and AIDS

View full text Add to dashboard Cite

Purpose of review As optimized antiretroviral therapy (ART) regimens are prepared for introduction in low and middle income countries (LMIC), we consider the current evidence related to dosing, efficacy and safety during pregnancy and breastfeeding of next generation first- and second-line ART regimens proposed for imminent introduction in the global marketplace. Recent findings Pregnancy pharmacokinetic considerations include potentially insufficient efavirenz exposure if dosed at 400mg/day, the need for twice daily darunavir dosing and the paucity of data related to tenofovir alafenamide and dolutegravir dosing, safety and efficacy. Increasingly evidence suggests an association with adverse birth outcomes, particularly in women conceiving on ART, and with varying risk by drug and drug combination. Clinical trials and studies are in progress or planned that aim to determine dosing, safety and efficacy of several new antiretrovirals. Summary Having a universal, highly potent and safe ART regimen for all individuals living with HIV in LMIC including pregnant women is clearly the most beneficial strategy to keep mothers alive and healthy and to prevent transmission of HIV to their children. It will have to be determined whether use of this next generation of optimized antiretrovirals will also optimize health outcomes of pregnant women and their children.

show abstract

Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women*

Cited by 41 publications

References 15 publications

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

Pharmacokinetics of Once Versus Twice Daily Darunavir in Pregnant HIV-Infected Women

Toward a universal antiretroviral regimen

Contact Info

Product

Resources

About