Clinical pharmacology of HIV protease inhibitors in pregnancy

Colbers, Angela; Burger, David M.

doi:10.1097/coh.0b013e3283136cc5

Cited by 13 publications

(10 citation statements)

References 27 publications

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confidence: 99%

“…Protease inhibitors (PIs) are widely used during pregnancy for both treatment and prevention of MTCT due to their efficacy, lack of CD4 count-dependent toxicity, and short half-lives (t 1/2 s). However, plasma concentrations of certain protease inhibitors have repeatedly been shown to be significantly reduced during the third trimester, with some concerns over efficacy (37).Lopinavir (LPV)-ritonavir (RTV), or LPV/r, is used during pregnancy, as it is potent and well tolerated and has no obvious human teratogenic effects (28). A number of studies report reduced LPV exposure during the third trimester of pregnancy in patients receiving standard dosing of the LPV/r soft-gel capsule (3 SGC; 400/100 mg twice daily) than in the same subjects postpartum and nonpregnant historical controls (1,22,29,30,34).…”

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Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Else

Douglas

Dickinson

et al. 2012

Antimicrob Agents Chemother

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Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC 0 -12 ) and maximum concentration were ϳ15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.A ntiretroviral therapies (ARTs), with the exception of zidovudine, are unlicensed for use in pregnancy. However, they are widely used, in accordance with national and international guidelines, both for maternal treatment and for the prevention of HIV mother-to-child transmission (MTCT). Multiple physiological changes which can impact the pharmacokinetics (PKs) of these agents occur during pregnancy; therefore, studies in pregnancy are required to ensure appropriate dosing and avoid unnecessary toxicity or treatment failure. Protease inhibitors (PIs) are widely used during pregnancy for both treatment and prevention of MTCT due to their efficacy, lack of CD4 count-dependent toxicity, and short half-lives (t 1/2 s). However, plasma concentrations of certain protease inhibitors have repeatedly been shown to be significantly reduced during the third trimester, with some concerns over efficacy (37).Lopinavir (LPV)-ritonavir (RTV), or LPV/r, is used during pregnancy,...

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confidence: 99%

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Else

Douglas

Dickinson

et al. 2012

Antimicrob Agents Chemother

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“…Changes in drug pharmacokinetics (PK) in the second and third trimesters could cause reductions in plasma exposure of several antiretrovirals, 1 while for most recent compounds few data are available. Boosted darunavir is widely used in multidrug-experienced pregnant patients, but information in this setting is limited to heterogeneous case reports showing lower trough concentrations (1168-1908 ng/mL) as compared with non-pregnant patients.…”

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Transplacental passage of etravirine and maraviroc in a multidrug-experienced HIV-infected woman failing on darunavir-based HAART in late pregnancy

Calcagno

Trentini

Marinaro

et al. 2013

Journal of Antimicrobial Chemotherapy

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“…Dosing of PIs in pregnancy is not well validated, with evidence of reduced plasma concentrations with several agents, especially when used unboosted [95, 96]. Recent findings suggest that in the absence of TDM, LPV/r dose should be increased 50% in the second and third trimesters of pregnancy [97].…”

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confidence: 99%

Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings

Peterson

Jallow

Rowland‐Jones

et al. 2011

AIDS Research and Treatment

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HIV-2 contributes approximately a third to the prevalence of HIV in West Africa and is present in significant amounts in several low-income countries outside of West Africa with historical ties to Portugal. It complicates HIV diagnosis, requiring more expensive and technically demanding testing algorithms. Natural polymorphisms and patterns in the development of resistance to antiretrovirals are reviewed, along with their implications for antiretroviral therapy. Nonnucleoside reverse transcriptase inhibitors, crucial in standard first-line regimens for HIV-1 in many low-income settings, have no effect on HIV-2. Nucleoside analogues alone are not sufficiently potent enough to achieve durable virologic control. Some protease inhibitors, in particular those without ritonavir boosting, are not sufficiently effective against HIV-2. Following review of the available evidence and taking the structure and challenges of antiretroviral care in West Africa into consideration, the authors make recommendations and highlight the needs of special populations.

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Clinical pharmacology of HIV protease inhibitors in pregnancy

Cited by 13 publications

References 27 publications

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

Transplacental passage of etravirine and maraviroc in a multidrug-experienced HIV-infected woman failing on darunavir-based HAART in late pregnancy

Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings

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