Use of pharmacotherapy during pregnancy is common and increasing. Physiologic changes during pregnancy may significantly alter the overall systemic drug exposure, necessitating dose changes. A search of PubMed for pharmacokinetic clinical trials showed 494 publications during pregnancy out of 35,921 total pharmacokinetic published studies (1.29%), from the late 1960s through August 31, 2013. Closer examination of pharmacokinetic studies in pregnant women published since 2008 (81 studies) revealed that about a third of the trials were for treatment of acute labor and delivery issues, a third included studies of infectious disease treatment during pregnancy, and the remaining third were for varied ante-partum indications. Approximately, two-thirds of these recent studies were primarily funded by government agencies worldwide, one-quarter were supported by private non-profit foundations or combinations of government and private funding, and slightly <10% were supported by pharmaceutical industry. As highlighted in this review, vast gaps exist in pharmacology information and evidence for appropriate dosing of medications in pregnant women. This lack of knowledge and understanding of drug disposition throughout pregnancy place both the mother and the fetus at risk for avoidable therapeutic misadventures – suboptimal efficacy or excess toxicity – with medication use in pregnancy. Increased efforts to perform and support obstetric dosing and pharmacokinetic studies are greatly needed.

Background. The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children.Methods. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine.Results. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations.Conclusions. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.

Background Maternal-fetal transfer of antiretroviral drugs contributes to prevention of vertical transmission of HIV. Objective This systematic review discusses published studies containing data pertaining to the pharmacokinetics of placental transfer in humans, including paired cord and maternal plasma samples collected at the time of delivery as well as ex vivo placental perfusion models. Methods Articles pertaining to placental transfer of antiretrovirals were identified from PubMed, from references of included articles, and from U.S. Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission guidelines. Articles from non-human animal models or that had no original maternal-fetal transfer data were excluded. PRISMA guidelines were followed. Results A total of 103 published studies were identified. Data across studies appeared relatively consistent for the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleotide reverse transcriptase inhibitors (NNRTIs), with cord to maternal ratios approaching 1 for many of these agents. The protease inhibitors atazanavir and lopinavir exhibited consistent maternal-to-fetal transfer across studies, although the transfer may be influenced by variations in drug-binding proteins. The protease inhibitors indinavir, nelfinavir, and saquinavir exhibited unreliable placental transport, with cord blood concentrations that were frequently undetectable. Limited data, primarily from case reports, indicate that darunavir and raltegravir provide detectable placental transfer. Conclusion These findings appear consistent with current guidelines of using two NRTIs plus an NNRTI, atazanavir/ritonavir, or lopinavir/ritonavir to maximize placental transfer as well as to optimally suppress maternal viral load. Darunavir/ritonavir and raltegravir may reasonably serve as second-line agents.

These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMP-SMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of piperaquine.

This prospective trial investigated the population pharmacokinetics of piperaquine, given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard three-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three-compartment model with first-order absorption described the data well. Age had a statistically significant effect (p<0.005) on clearance/bioavailability in a model that accounts for allometric scaling. Simulations demonstrated that higher doses in all children, but especially in those with lower weight for age, are required for adequate piperaquine exposure, though safety and tolerance will need to be established. These findings support other evidence that both weight and age-specific guidelines for piperaquine dosing in children are urgently needed.

This study aims to evaluate the safety, acceptability, and pharmacokinetics (PK) of an increased dose of nelfinavir (NFV) during the third trimester of pregnancy. The study was registered as part of the International Maternal Pediatric Adolescent AIDS Clinical Trials network (IMPAACT-P1026s), an ongoing multicenter prospective cohort study of antiretroviral PK during pregnancy (NCT00042289). NFV intensive PK evaluations were performed at steady state during the third trimester of pregnancy and 2-3 weeks postpartum. Plasma concentrations of NFV and its active metabolite, hydroxyltert-butylamide (M8) were measured using high-performance liquid chromatography with ultraviolet detection. A total of 18 women are included in the analysis. NFV area under the concentration-time curve (AUC) with the increased dose during the third trimester was nearly identical to the standard dose postpartum, with a geometric mean ratio for third trimester to postpartum AUC of 0.98 (90%CI 0.71-1.35). Despite the increased dose, M8 AUC was lower during the third trimester compared to postpartum (0.53, IQR [0.38-0.75]), as was the M8/NFV AUC ratio (0.51, IQR [0.42-0.63]). NFV AUC 0-12 was above target in 15 of 18 (83%) of participants during the third trimester compared to 14 of 16 (88%) postpartum. No major safety concerns were noted. Increasing the NFV dose to 1875 mg twice daily during the third trimester achieved similar concentrations postpartum compared to standard dosing (1250 mg twice daily). Increased NFV dose regimens may still have some benefit to human immunodeficiency virus (HIV)-positive pregnant women living in countries where novel protease inhibitors are currently unavailable or in individuals who are intolerant to ritonavir-boosted HIV medications.

Hepatitis C virus genotype 6 patients should be treated for 48 weeks, and those who achieve RVR may receive the shorter 24-week treatment duration. The high SVR (~80 %) with 48 weeks of PEG IFN+RBV therapy may be a cost-effective option for HCV-6 patients from resource-poor regions.

Objective: Our goal was to systematically and quantitatively assess treatment response between Asian patients with hepatitis C virus genotype 6 (HCV-6) and hepatitis C virus genotype 1 (HCV-1) treated for 48 weeks with pegylated interferon and ribavirin. Methods: We performed a literature search in MEDLINE and EMBASE for ‘genotype 6' in August 2013. Additional abstracts from major international scientific conferences from 2012 to 2013 were reviewed. Studies included were original articles with ≥10 treatment-naïve Asian HCV-6 patients. Exclusion criteria were coinfections with hepatitis B virus, HIV and/or other liver diseases. Heterogeneity was defined as a Cochrane Q test with a p value of 0.10 and an I² statistic of >50%. Results of a random-effects model are reported. Results: A total of 1,046 (503 HCV-6; 543 HCV-1) patients from 12 studies were included in the analysis. The pooled sustained virologic response (SVR) rate was 80.2% (95% CI 74.3-85.0, Q statistic = 20.87, p < 0.035; I² = 47.3%) for HCV-6 and 62.5% (95% CI 41.9-79.4, Q statistic = 52.41, p < 0.001; I² = 92.37) for HCV-1 patients. HCV-6 patients had a significantly higher SVR rate compared to HCV-1 patients (odds ratio 2.73, 95% CI 1.69-4.41, p < 0.001). Approximately one fourth of patients without early virologic response (EVR) achieved SVR, regardless of genotype (HCV-1, n = 6/23; HCV-6, n = 4/21). Conclusions: Asian patients with HCV-6 can expect higher SVR rates (∼80%) than HCV-1 patients (∼63%). EVR as a stopping rule is less clear in Asian patients with HCV-6 and HCV-1.