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Nelfinavir Plasma Concentrations Are Low during Pregnancy
  Clinical Infectious Diseases
Sept 1, 2004;39:736-740
Jeannine F. J. B. Nellen,1 Igor Schillevoort,2 Ferdinand W. N. M. Wit,1,2 Alina S. Bergshoeff,4 Mieke H. Godfried,1 Kees Boer,3 Joep M. A. Lange,1,2 David M. Burger,4 and Jan M. Prins1
1Academic Medical Center, Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine, and AIDS, 2International Antiviral Therapy Evaluation Center, and 3Department of Gynecology and Obstetrics, University of Amsterdam, Amsterdam; and 4Department of Clinical Pharmacy, University Medical Centre, Nijmegen, The Netherlands
Plasma nelfinavir concentration ratios (CRs) were calculated for all pregnant (n = 27) and non-pregnant (n = 48) human immunodeficiency virus type 1-infected women receiving the drug who visited our outpatient clinic.
In pregnant women, mean and median nelfinavir CRs were significantly lower (P = .02 and P = .04, respectively), and 51% of the CRs were below the clinically relevant threshold of 0.90, compared with 35% of the CRs in non-pregnant women.
After we adjusted for confounders, we found that the mean nelfinavir CR was 34% lower in pregnant women (P = .02). With targeted interventions, subsequent CRs in pregnant women showed a significant increase (median increase, 0.31; P = .01).
HAART is recommended in pregnant, HIV-1infected women to reduce vertical HIV-1 transmission. Nelfinavir combined with 2 nucleoside analogue reverse-transcriptase inhibitors is frequently used because of its safety, efficacy, and favorable side-effect profile. It is well tolerated in pregnant women. Diarrhea seldom occurs, maybe due to the tendency toward constipation during pregnancy.
Pregnancy is accompanied by a variety of physiological changes that affect drug pharmacokinetics, particularly in the third trimester. The overall effect of pregnancy on the pharmacokinetics of a particular drug cannot easily be predicted. Low plasma nelfinavir concentrations (i.e., concentration ratios [CRs] of <0.90) are strongly associated with an increased risk of virological failure.
A preliminary report showed a nelfinavir exposure level below the target area under the curve (AUC) in 3 of 17 pregnant women and significantly lower antepartum levels than postpartum levels. Another report was not conclusive because it showed conflicting results between pregnant patients. The aim of this study was to assess whether plasma concentrations of nelfinavir are influenced by pregnancy.
CRs were significantly lower in pregnant women, compared with nonpregnant women. Vertical transmission is highly correlated with maternal plasma HIV load, and transmission is most likely to occur during delivery. Low nelfinavir CRs during pregnancy potentially increase the risk of viremia during delivery because of a slow decline of the plasma HIV load or virological treatment failure. CRs of nelfinavir show large variability. Poor adherence, failure to take the drug with food, and inaccurate recall of the time of dosing are potential factors explaining this variability. CRs of nelfinavir of <0.90 are associated with virological failure. There are no reasons to believe that this association is different during pregnancy.
The nelfinavir CRs were particularly low during the third trimester. After adjustment for confounders identified in the univariate analysis, pregnancy remained significantly associated with low nelfinavir CRs. Because of a possible reverse causality of a low plasma nelfinavir CR on the plasma HIV load and the CD4 cell count, we corrected for hepatitis C infection only, and the association remained. The presence of chronic infection with hepatitis C virus probably decreases the hepatic clearance of nelfinavir, thereby increasing the plasma levels of nelfinavir. Sex, age, and body weight have already been proven to be of no influence on plasma concentrations. Nonpregnant women had a mean CR comparable to that of the reference population. Diarrhea has been identified as a cause of low nelfinavir CRs, but none of the pregnant women had diarrhea. We have no data on adherence, but adherence rates are, in our experience, higher during pregnancy, because pregnant women are highly motivated to take HAART to prevent HIV infection in their babies.
It is uncertain how these lower nelfinavir CRs during pregnancy should be explained. Because nelfinavir is metabolized by the enzyme CYP450, increased hepatic elimination caused by enzyme induction during pregnancy is a possible mechanism. CYP3A4, the major enzyme in nelfinavir metabolism, is upregulated during pregnancy. The activity of CYP2C19 is also upregulated, so, theoretically, the low plasma nelfinavir concentration might be compensated for by an increased concentration of M8, the pharmacologically active metabolite. However, M8 levels were also significantly lower in pregnant women, compared with nonpregnant women. In women receiving therapy with indinavir and saquinavir (soft gel capsule formulation), there are also indications that the plasma AUC is decreased during pregnancy.
Nelfinavir is highly (>98%) protein-bound. Pregnancy leads to a decreased protein-binding capacity, so, theoretically, a decreased total nelfinavir concentration might be compensated for by a higher free nelfinavir fraction. Unfortunately, the free fraction of nelfinavir is difficult to quantify because it is below the detection limit (i.e., 0.04 mg/L) of the currently available assays.
Until further evidence about free plasma drug concentrations becomes available, the target nelfinavir CR during pregnancy should remain 0.90. This can be reached with interventions such as emphasis on adherence and the need for intake with sufficient food or an increase in the dose of nelfinavir.
In conclusion, nelfinavir CRs are low during pregnancy, which increases the risk of not having a plasma HIV-RNA load of <50 copies/mL at the time of delivery. Close monitoring of plasma concentrations is, therefore, warranted during pregnancy, and, in situations in which the time to reach an undetectable viral load is limited (e.g., diagnosis of HIV late in pregnancy), one should consider the option of starting therapy with nelfinavir at a dosage of 1500 mg b.i.d.
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