Zhaoxia Ren

Pharmacokinetics of oseltamivir among pregnant and nonpregnant women

We sought to delineate the pharmacokinetics (PK) of oseltamivir and its active metabolite oseltamivir carboxylate during pregnancy. Physiologic changes of pregnancy, including increased renal filtration and secretion, may increase the clearance of oseltamivir carboxylate. Sixteen pregnant women taking oseltamivir for prophylaxis or treatment of suspected/proven influenza infection were enrolled. Twenty-three nonpregnant reproductive-age females served as the control group. The primary PK endpoint was area under the plasma concentration time curve for oseltamivir carboxylate. Pregnancy did not alter the PK parameters of the parent compound, oseltamivir. However, for oseltamivir carboxylate the area under the plasma concentration time curve was significantly lower (P = .007) and the apparent clearance significantly higher (P = .006) in pregnant women compared with nonpregnant women. Pregnancy produces lower systemic levels of oseltamivir carboxylate. Increasing the dose and/or dosing frequency of oseltamivir during pregnancy may be necessary to achieve comparable exposure in pregnant and nonpregnant women.

Special Challenges In Comparative Effectiveness Research On Children’s And Adolescents’ Health

The United States is undertaking a major expansion of comparative effectiveness research, with the potential to achieve systemwide improvements in health care quality, outcomes, and resource allocation. However, to achieve these improvements in childrens health and health care, comparative effectiveness research needs to be targeted, designed, conducted, and reported in ways that are responsive to the unique circumstances of children and adolescents. These include clinically important differences in the type and course of disease in children; demographic differences between the overall child and adult population in the United States, such as racial and ethnic makeup; and methodological issues involving study design. Our overarching point is that the base of evidence in pediatrics must not fall even further behind that for the adult population in an era of rapid advancement and funding of comparative effectiveness research.

Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases.

Most autoimmune and systemic inflammatory diseases are more common in women than in men, including women of child-bearing age. Therefore, for many of our patients, family planning is an important clinical issue. The management of pregnancy in autoimmune diseases is complex, benefitting optimally from a multidisciplinary approach that takes into consideration: prepregnancy counseling; treatments received prior to, during, and after pregnancy; early recognition of both obstetric complications and medical complications relating to the underlying disease; prenatal fetal development; and postnatal management of the

Review of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act: What can the obstetric community learn from the pediatric experience?

Children have been called therapeutic orphans as they have been excluded from drug research and new drug development resulting in the lack of proper labels for majority of the drugs for pediatric use. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are two legislative mandates to improve pediatric drug labeling. The BPCA legislation authorizes the National Institutes of Health (NIH) to implement research programs through funding clinical trials to study off-patent drugs in pediatric population. Obstetric pharmacology research gaps are in many ways similar to those in pediatrics, including off-label use of common medications, and lack of knowledge of appropriate dosing, safety, and efficacy of drugs. Much research is needed to define mechanisms of disease and drug actions in pregnant women to fill the knowledge gaps.

Fluconazole Prophylaxis for the Prevention of Candidiasis in Premature Infants: A Meta-analysis Using Patient-level Data

BACKGROUND Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. METHODS We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States. We obtained patient-level data from the study investigators and performed an aggregated analysis. The occurrence of each endpoint in infants who received prophylaxis with fluconazole vs placebo was compared. Endpoints evaluated were IC or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates. Safety endpoints evaluated included clinical and laboratory parameters. RESULTS Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30-.78), 0.20 (95% CI, .08-.51), and 0.28 (95% CI, .18-.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups. CONCLUSIONS Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women

AIMS Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. METHODS A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non-compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. RESULTS The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy. CONCLUSION Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women.

Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

Objective To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. Study design A total of 41 obese children (6‐17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ˜1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post‐dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. Results Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥12 years of age and markedly reduced in children <12 years of age. Conclusions LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age‐related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age. Trial registration ClinicalTrials.gov: NCT02186652

Impact of Pregnancy History and 17-Hydroxyprogesterone Caproate on Cervical Cytokines and Matrix Metalloproteinases

Objective The objective of this study was to evaluate the impact of pregnancy history and 17‐hydroxyprogesterone caproate (17‐OHPC) treatment on cervical fluid cytokines and matrix metalloproteinases (MMPs). Study Design Cervical fluid was obtained between 160/7 and 246/7 weeks from women with only prior term births (controls, n = 26), women with one or more prior spontaneous preterm births (SPTBs) choosing to receive 17‐OHPC (17‐OHPC, n = 24), or to not receive 17‐OHPC (refusers, n = 12). Cervical fluid collections were repeated 2, 4, and 8 weeks after the first sample and concentrations of MMPs and cytokines were measured by multiplex immune assay. Results Among women whose earliest prior delivery occurred between 16 and 23 weeks, cervical fluid concentration of interleukin (IL)‐6, IL‐10, and tumor necrosis factor (TNF)‐&agr; at baseline were significantly elevated when compared with cervical cytokines of women whose earliest delivery occurred between 32 and 36 weeks (relative risk ratio was 3.37 for IL‐6 [95% confidence interval, CI, 1.08–10.53, p < 0.05], 2.81 for IL‐10 [95% CI, 1.39–5.70, p < 0.05], and 6.34 for TNF‐&agr; [95% CI, 2.19–18.68, p < 0.001]). Treatment with 17‐OHPC had no significant impact on these cytokines. Conclusion The cervical fluid of women with a history of an early prior SPTB is characterized by inflammation that is unaffected by 17‐OHPC.