The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum

Heeswijk, Rolf P. G. van; Khaliq, Yasmin; Gallicano, Keith; Bourbeau, Marc; Seguin, Isabelle; Phillips, Elizabeth; Cameron, D. William

doi:10.1016/j.clpt.2004.08.011

Cited by 65 publications

(63 citation statements)

References 37 publications

(81 reference statements)

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“…Some researchers have provided evidence of a postpartum drop in metabolic capacity that could result in briefly elevated drug concentrations (i.e., higher than baseline) for some antidepressants during the first 6–8 weeks following delivery 20, 21, 22, 23, 24. Due to few postpartum observations our study can neither confirm nor rule out that such a refractory period occurs for antipsychotic agents.…”

Section: Discussionmentioning

confidence: 61%

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (−76%; confidence interval (CI), −83%, −66%; P < 0.001) and aripiprazole (−52%; CI, −62%, −39%; P < 0.001), but not for olanzapine (−9%; CI, −28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

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Section: Discussionmentioning

confidence: 61%

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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“…Nellen et al (19) found that the mean nelfinavir concentration ratio was significantly lower in pregnant women. Van Heeswijk et al (24) reported a significant reduction in nelfinavir minimum plasma concentration, supported by an Angel et al (2) study showing a 2.5-fold increase in nelfinavir apparent oral clearance. However, these studies included a small number of pregnant women.…”

Section: /F) 355 Liters/h (50%); Apparent Volume Of Distribution (Vmentioning

confidence: 53%

Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

Hirt¹,

Tréluyer²,

Jullien³

et al. 2006

Antimicrob Agents Chemother

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A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. 59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h؊1 ) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor used in highly active antiretroviral therapy. It has been widely used in pregnancy as therapy for the woman's own HIV infection as well as for the prevention of mother-tochild transmission because of its tolerability and potency. However, the physiological changes associated with pregnancy can lead to important variations in pharmacokinetic processes of absorption, distribution, and elimination. The oral bioavailability of nelfinavir is highly variable in adults (20 to 80%) and increases two-to threefold when administered with food (Viracept package insert, 2001; Agouron Pharmaceuticals, La Jolla, Calif.). The nelfinavir apparent volume of distribution is 2 to 7 liters/kg of body weight. Nelfinavir is metabolized into the active metabolite hydroxy-tert-butylamide (M8) via the CYP2C19 enzyme, and both drugs are metabolized via CYP3A4 (14, 25). It was reported that pregnant women have lower nelfinavir plasma concentrations than nonpregnant women. Nellen et al. (19) found that the mean nelfinavir concentration ratio was significantly lower in pregnant women. Van Heeswijk et al. (24) reported a significant reduction in nelfinavir minimum plasma concentration, supported by an Angel et al. (2) study showing a 2.5-fold increase in nelfinavir apparent oral clearance. However, these studies included a small number of pregnant women. A po...

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“…HIV protease inhibitor drug levels are generally reduced during pregnancy [13][14][15][16], especially during the third trimester, because of metabolic and physiological changes associated with pregnancy [17]. In one study of lopinavir/RTV, compensation for the lower exposures required a dose increase to 533/133 mg twice daily (bid) from 400/100 mg bid in the third trimester to produce exposures similar to those in nonpregnant historical controls [7].…”

Section: Introductionmentioning

confidence: 99%

“…Atazanavir (ATV) is a potent, well-tolerated, once-daily (qd) HIV protease inhibitor, with established efficacy in both treatment-naïve and treatment-experienced adult, nonpregnant HIV-infected patients [11,12] and is included as a preferred treatment option for nonpregnant HIVinfected patients [2]. HIV protease inhibitor drug levels are generally reduced during pregnancy [13][14][15][16], especially during the third trimester, because of metabolic and physiological changes associated with pregnancy [17]. In one study of lopinavir/RTV, compensation for the lower exposures required a dose increase to 533/133 mg twice daily (bid) from 400/100 mg bid in the third trimester to produce exposures similar to those in nonpregnant historical controls [7].…”

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confidence: 99%

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

et al. 2011

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ObjectiveThere are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women. MethodsIn this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/ 100 mg (n 5 20) or 400/100 mg (n 5 21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C max ), trough observed plasma concentration 24 hour post dose (C min ) and area under concentration-time curve in one dosing interval (AUC t )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n 5 23). ResultsAt or before delivery, all mothers achieved HIV RNA o50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC t for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C min values were comparable. The C min value for atazanavir/RTV 400/100 mg was 39% higher than the C min for atazanavir/RTV 300/100 mg in historical controls, but the AUC t values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (42.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events. ConclusionsIn this study, use of atazanavir/RTV 300/100 mg qd produced C min comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV.Keywords: atazanavir, HIV, pregnancy, prevention of mother-to-child transmission, protease inhibitor IntroductionTreatment guidelines for HIV-1 infection in pregnant women recommend highly active antiretroviral (ARV) therapy (HAART) with two nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine) plus the nonnucleoside reverse transcriptase inhibitor nevirapine [1][2][3]. Some guidelines also recommend the ritonavir (RTV)-boosted protease inhibitor lopinavir as an optional third agent [1], although others recommend several boosted protease inhibitors as optional agents [2]. All other ARV DOI: 10.1111/j.1468-1293.2011.00927.x HIV Medicine (2011 r 2011 British HIV Association 570 drugs are alternative agents or for use in special circumstances [1,4]. However, there are questions and concerns regarding the two most frequently recommended third agents: treatment initiation with nevirapine is associated with an increased risk of symptomatic liver toxicity, often accompanied by a rash, which is potentially fatal [1,5]. Concerns with RTV-boosted lopinavir inclu...

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The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum

Cited by 65 publications

References 37 publications

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women

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