Pharmacokinetics during pregnancy: evidence-based maternal dose formulation

140

c Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series. Children under the age of 5 years and pregnant women are especially vulnerable to malaria. An estimated 85 million pregnancies occurred in areas with falciparum malaria transmission during 2007 (13). Malaria during pregnancy is responsible for maternal and fetal mortality (42,43). Both falciparum malaria and vivax malaria during pregnancy are associated with low birth weight resulting from intrauterine growth restriction (8, 9, 48). Effective treatment and prophylaxis of malaria in pregnancy rely on the use of efficacious antimalarial drugs.Pregnancy has substantial effects on the pharmacokinetic characteristics of many antimalarial drugs. Previous studies report artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, cycloguanil, pyrimethamine, and lumefantrine concentrations to be reduced in pregnant women (25,33,34,36,44,58). This may contribute to lower antimalarial cure rates in pregnant than nonpregnant adults (58). Other studies report no pharmacokinetic differences in pregnant women compared to nonpregnant women (e.g., pyrimethamine and amodiaquine/desethylamodiaquine) or even a higher drug exposure during pregnancy (pyrimethamine) (15,25,46).Artemisinin-based combi...

Section: Figmentioning

confidence: 65%

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

Tärning

Rijken

McGready

et al. 2012

140

“…It is possible that the women in the Thai study, whether pregnant or not, consumed increasing amounts of fat as they recovered from malaria, progressively increasing bioavailability as a result of the lipophilicity of PQ. It is also possible that the greater time-independent relative bioavailability in the pregnant versus nonpregnant women in the Thai study represented pregnancyassociated physiological changes favoring PQ absorption, including reduced small intestine motility, prolonged gastric emptying, and increased intestinal blood flow (14,53,54), which are of pharmacokinetic significance after consumption of food but not in the fasting state.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

Benjamin

Moore

Salman

et al. 2015

The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC 0 -ؕ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.

“…It is well established that the pharmacokinetics of drugs may be altered during pregnancy (9,10). Factors that may lead to pregnancy-induced changes in drug absorption and disposition include increased gastric and intestinal emptying times, reductions in the levels of gastric acid secretion, increases in the levels of mucus secretion, plasma volume expansion, increased cardiac output, changes in organ blood flow, stimulation of hepatic microsomal enzymes, and inhibition of microsomal oxidases.…”

mentioning

confidence: 99%

Pharmacokinetics of Saquinavir plus Low-Dose Ritonavir in Human Immunodeficiency Virus-Infected Pregnant Women

Acosta

Bardeguez

Zorrilla

et al. 2004

The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng ⅐ h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC 12 s) during gestation (29,373 ؎ 17,524 ng ⅐ h/ml [mean ؎ standard deviation]), during labor and delivery (26,189 ؎ 22,138 ng ⅐ h/ml), and during the postpartum period (35,376 ؎ 26,379 ng ⅐ h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC 12 , 7,811 and 13,127 ng ⅐ h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P < 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.It is well established that the pharmacokinetics of drugs may be altered during pregnancy (9, 10). Factors that may lead to pregnancy-induced changes in drug absorption and disposition include increased gastric and intestinal emptying times, reductions in the levels of gastric acid secretion, increases in the levels of mucus secretion, plasma volume expansion, increased cardiac output, changes in organ blood flow, stimulation of hepatic microsomal enzymes, and inhibition of microsomal oxidases. Many of these physiologic changes begin during the second trimester and become marked during the third trimester. These changes make prediction of the effect of pregnancy on the pharmacokinetics of drugs difficult.Considerable data indicate that there is a significant association between antiretroviral drug concentrations and the virologic response or toxicity, particularly for the protease inhibitor...