Nelfinavir Plasma Concentrations Are Low during Pregnancy

Nellen, Jeannine; Schillevoort, Igor; Wit, Ferdinand W. N. M.; Bergshoeff, Alina S.; Godfried, Mieke H.; Boer, Kees; Lange, Joep M. A.; Burger, David M.; Prins, Jan M.

doi:10.1086/422719

Cited by 37 publications

(27 citation statements)

References 17 publications

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“…The macaque reproduced the pregnancy-associated changes in the disposition of oral NFV observed in pregnant women (Nellen et al, 2004;van Heeswijk et al, 2004). In the macaque, the maximum plasma concentration and the dosenormalized AUC after oral NFV were significantly decreased ϳ68% by pregnancy (Table 1).…”

Section: Discussionmentioning

confidence: 69%

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As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

Huixia¹,

Wu²,

Chung³

et al. 2009

J Pharmacol Exp Ther

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The apparent oral clearance of protease inhibitors (PIs) is increased in pregnant women. Although this phenomenon is reproduced in the mouse, because of the multiplicity of mouse cytochrome P450 isoforms, lack of information on their substrate and inhibitor selectivity, and lack of reagents (e.g., antibodies, purified protein), it is difficult to study the mechanistic basis of this phenomenon in this animal model. To investigate the mechanistic basis of this phenomenon in a more representative model, the nonhuman primate, we first determined whether this phenomenon could be reproduced in Macaca nemestrina, using nelfinavir as a model PI. Consistent with the human and mouse studies, we found that the apparent oral clearance of nelfinavir (NFV) in the macaques was significantly increased (3.14-fold) antepartum (n ϭ 3) versus postpartum (n ϭ 4). This increased apparent oral clearance was a result of an increased systemic clearance (1.9-fold) and a decreased bioavailability (ϳ45%) during pregnancy. In vitro, pregnancy significantly enhanced the rate of NFV depletion in hepatic, but not intestinal S-9 fractions. Human CYP3A inhibitors erythromycin (0.5 mM), ketoconazole (0.5 M), and troleandomycin (0.01-1 mM), but not the CYP2C inhibitor, sulfaphenazole (3 M), significantly inhibited the depletion of NFV in hepatic S-9 fractions and expressed rhesus CYP3A64 enzyme. Based on these data, we conclude that increased hepatic activity of NFV-metabolizing enzymes (perhaps CYP3A enzymes) results in increased clearance of PIs during pregnancy in the macaques. The M. nemestrina should be further investigated as a model to study the mechanisms by which the clearance of PIs is increased during pregnancy.Protease inhibitors (PIs) are a class of antiretroviral agents that inhibit protease activity of HIV, thus preventing the postintegration step in HIV replication. For the treatment of the HIV-infected pregnant women and to prevent mother-toinfant HIV transmission, current antiretroviral guidelines recommend triple combination highly active antiretroviral therapy (Centers for Disease Control and Prevention, 1998). Because of its safety, tolerability, and potency, nelfinavir (NFV), together with nucleoside/non-nucleoside reverse transcriptase inhibitors, is the recommended treatment for pregnant women infected with HIV (Mofenson, 2003;Thorne and Newell, 2004).HIV PIs, among several other classes of drugs, have altered pharmacokinetics during pregnancy (Anderson 2005). Several studies have shown that given the standard dosing regimen, pregnant women achieve lower PI plasma concentrations than nonpregnant women. For example, we have observed that the exposure of antepartum women to indinavir is 68% lower than during the postpartum period (Unadkat et al., 2007). In addition, pregnant women taking saquinavir have approximately 77% lower exposure [area

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Section: Discussionmentioning

confidence: 69%

“…Likewise, the antepartum exposure to NFV is ϳ25% lower in pregnant versus postpartum women (Angel et al, 2001;Nellen et al, 2004;van Heeswijk et al, 2004). Likewise, steady-state plasma concentrations and exposure to ritonavir are ϳ40% lower in pregnant versus postpartum women (Acosta et al, 2004).…”

mentioning

confidence: 99%

As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

Huixia¹,

Wu²,

Chung³

et al. 2009

J Pharmacol Exp Ther

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“…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.…”

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

confidence: 98%

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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“…Several studies have indicated that pregnancy considerably reduces the exposure of these women to protease inhibitors (PIs) such as nelfinavir and saquinavir, compared with that of men, nonpregnant women, or postpartum women administered an equivalent dose of the drug (Angel et al, 2001;Acosta et al, 2004;Nellen et al, 2004). This reduction in exposure, as measured by plasma area under the curve or mean/median concentration ratio, is in the order of 70 to 90% compared with postpartum or nonpregnant controls.…”

mentioning

confidence: 99%

Effect of Pregnancy on Cytochrome P450 3a and P-Glycoprotein Expression and Activity in the Mouse: Mechanisms, Tissue Specificity, and Time Course

Zhang

Wang

et al. 2008

Mol Pharmacol

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The plasma concentrations of orally administered anti-human immunodeficiency virus protease inhibitors are significantly reduced during human and mouse pregnancy. We have shown that in the mouse, at gestational day 19, this reduction is due to increased hepatic cytochrome P450 3a (Cyp3a) protein expression and activity. In the current study, we investigated the mechanisms by which Cyp3a activity is increased by pregnancy and the time course of change in expression of Cyp3a and P-glycoprotein (P-gp) in various tissues. We found that hepatic transcripts of Cyp3a16, Cyp3a41, and Cyp3a44 were significantly increased during pregnancy, whereas those of Cyp3a11 and Cyp3a25 were significantly decreased. This resulted in a net increase in Cyp3a protein expression and activity in the liver during pregnancy. The increase in Cyp3a41 and Cyp3a44 transcripts was positively correlated (p Ͻ 0.05) with hepatocyte nuclear factor 6 and estrogen receptor-␣ transcripts. The pregnancy-related factors that transcriptionally activated mouse Cyp3a isoforms also activated the human CYP3A4 promoter in pregnant CYP3A4-promoter-luciferase transgenic (CYP3A4-tg) mice. In contrast, intestinal Cyp3a protein expression was not significantly affected by pregnancy. No change in P-gp protein expression was observed in the liver or kidney during pregnancy, although a significant decrease was observed in the placenta. Because hepatic CYP3A activity also seems to be induced during human pregnancy, the mouse (including CYP3A4-tg mouse) seems to be an excellent animal model to determine the molecular mechanisms for such an induction.To treat the pregnant woman and to prevent maternalfetal HIV-1 transmission, HIV-1-infected pregnant women are routinely prescribed anti-HIV protease inhibitors as part of their highly active antiretroviral therapy regimen (Mofenson, 2003;Thorne and Newell, 2005). Several studies have indicated that pregnancy considerably reduces the exposure of these women to protease inhibitors (PIs) such as nelfinavir and saquinavir, compared with that of men, nonpregnant women, or postpartum women administered an equivalent dose of the drug (Angel et al., 2001;Acosta et al., 2004;Nellen et al., 2004). This reduction in exposure, as measured by plasma area under the curve or mean/median concentration ratio, is in the order of 70 to 90% compared with postpartum or nonpregnant controls. Likewise, a perinatal study (PACTG 358) we have conducted in HIV-1-infected pregnant women has shown that the plasma area under the curve of indinavir is 73% lower antepartum (31 weeks) than that observed in the same women 6 weeks postpartum (Unadkat et al., 2007).The bioavailability and systemic clearance of the PIs are primarily determined by the drug-metabolizing enzymes cytochrome P450 3A4/5 (CYP3A4/5) and the drug efflux transporter P-glycoprotein (P-gp) in the small intestine and liver (Kim et al., 1998;van Heeswijk et al., 2001). Several studies have indicated that pregnancy increases the activity/expression of P-gp and/or CYP3A. Tracy et al....

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Nelfinavir Plasma Concentrations Are Low during Pregnancy

Cited by 37 publications

References 17 publications

As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

As in Humans, Pregnancy Increases the Clearance of the Protease Inhibitor Nelfinavir in the Nonhuman Primate Macaca nemestrina

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

Effect of Pregnancy on Cytochrome P450 3a and P-Glycoprotein Expression and Activity in the Mouse: Mechanisms, Tissue Specificity, and Time Course

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