Insufficient data inform dosing of antidepressants and clinical monitoring for major depressive disorder (MDD) during the perinatal period. The objectives were to assess the pharmacokinetics of sertraline (SER) across pregnancy and postpartum. Participants treated with SER for MDD underwent serial sampling to measure steady-state concentrations of SER and norsertraline during the second and third trimesters and postpartum (total of 3 assessments). Blood was drawn before observed SER administration and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. A sensitive high-performance liquid chromatography/mass spectrometric method for simultaneous determination of serum concentrations of SER and norsertraline was developed and validated. For each sampling period for SER, area under the serum concentration versus time curve, maximal serum concentration (Cmax), and the time at which Cmax occurred (Tmax) were determined. Of 11 women initially enrolled, 6 completed second- and third-trimester assessments, and 3 completed all 3 assessments (including the postpartum assessment). Mean changes on all pharmacokinetic parameters were nonsignificant between assessments, although there was a marked heterogeneity among individuals. Results were not significantly altered by incorporation of body weights into the analyses. The range of pharmacokinetic changes between individuals was broad, indicating heterogeneity regarding the impact of pregnancy on SER metabolism. Overall, lowest observed SER area under the curve and Cmax occurred in the third trimester (observed in 5 of 6 participants). Despite nonsignificant mean pharmacokinetic changes, the range of pharmacokinetic changes across pregnancy warrants careful monitoring of depressive symptoms in women with MDD in late pregnancy and further study.

Aiming to emulate the successful accelerated development of HIV/AIDS drugs, the Critical Path Institute (C-Path), in collaboration with the Engelberg Center for Health Care Reform at the Brookings Institution, has formed the Coalition Against Major Diseases (CAMD). Members include 6 nonprofit groups representing patients' interests, 15 leading pharmaceutical companies, the US Food and Drug Administration (FDA), the European Medicines Agency (EMEA), 2 institutes of the National Institutes of Health (NIH)-the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS)-and representatives from academia. The coalition's purpose is to transform the drug development paradigm for neurodegenerative diseases and serve as a model for other major diseases.

There are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6.

There are specific pharmacology issues related to women's unique physiology, including the hormonal changes that occur throughout their life span. Studies have shown alterations in drug metabolism in relation to phase of menstrual cycle, during pregnancy, or after menopause. In the brain, hormones can alter the response to drugs through various mechanisms. Estrogen and other compounds can bind to the estrogen receptor and modulate a wide range of activities within the cell. In addition, animal studies have demonstrated sexual dimorphism in the brain in terms of both the type of response to estrogen and the response as related to timing of administration. Many normal physiological changes that occur during pregnancy can affect pharmacokinetics and pharmacodynamics. These changes during pregnancy are dramatic rises in levels of estrogen and progesterone, increases in maternal blood volume, altered protein binding resulting from a drop in albumin levels, and a rise in levels of other plasma proteins. The field of chronobiology offers a way to study these changes in biological functions. Chronopharmacology is the study of how biological rhythms, particularly 24-hour, menstrual cycle, and annual rhythms, impact the pharmacokinetics and pharmacodynamics of drugs as a function of their timing. Chronopharmacokinetics is the study of the absorption, distribution, metabolism, and elimination of medicines according to the time of day, menstrual cycle, or year. In addition to applying chronobiology to the study of drugs used in women, new technologies were addressed from computer modeling, pharmacogenetics (genetics of the response to drugs), and in vivo drug metabolism studies.