Angela D. M. Kashuba

Preexposure Prophylaxis for HIV Infection among African Women

BACKGROUND Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others. METHODS In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety. RESULTS HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF-FTC group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the TDF-FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. CONCLUSIONS Prophylaxis with TDF-FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.).

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4+ T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Narrative Review: Antiretroviral Therapy to Prevent the Sexual Transmission of HIV-1

The magnitude of the HIV epidemic has exceeded the worst early predictions. At the end of 2005, the Joint United Nations Programme on HIV/AIDS (UNAIDS) (1) estimated that 38.6 million persons were infected worldwide (4.1 million were incident HIV cases) and that 2.8 million HIV-related deaths occurred in that year alone. Currently, no vaccine to prevent HIV exists and it is unlikely that one will be developed during the next few years. Accordingly, a series of other preventive measures embracing a combination of biological and behavioral approaches have been and are being explored, with some demonstrable positive results (2, 3). Among prevention options, the use of antiretroviral therapy (ART) is particularly attractive because antibiotics have successfully stopped the spread of many other diseases. Antiretroviral therapy has dramatically increased survival for HIV-infected patients (4) and prevented vertical transmission of HIV (5). Antiretroviral therapy could be used for preventing sexual transmission of HIV in 3 ways: 1) effective treatment of infected persons to reduce HIV transmission to sexual partners, 2) nonoccupational postexposure prophylaxis, and 3) preexposure prophylaxis. We provide a current view of each approach, including work in progress. Literature Search Strategy We searched the Cochrane Library and PubMed for relevant publications. We searched the Cochrane Library under the topic HIV/AIDS and then limited results by using the term biomedical prevention. We located a proposal to review the safety and efficacy of nonoccupational postexposure prophylaxis that was not yet completed. We searched PubMed by using the terms HIV and antiretroviral in the Medical Subject Heading (MeSH) database and then limited the results by using the terms prevention and control, transmission, and anti-retroviral agents. We reviewed publications retrieved from this search and selected those that we judged to be relevant. The MeSH terms are part of a distinct vocabulary created by the National Library of Medicine to index articles for MEDLINE and PubMed that provides a consistent way to retrieve information using different terminology. We also searched PubMed using the terms post-exposure, pre-exposure, prophylaxis, prevention, PEP, PREP, nPEP, and HIV. We primarily selected articles published within the past 5 years but did not exclude commonly referenced publications outside of this time period. We also reviewed abstracts from the 10th, 11th, 12th, and 13th Clinical Retrovirus and Opportunistic Infections (CROI) Conferences and the XIV and XVI International AIDS Conferences by using the terms mentioned. We included English-language articles only. We excluded studies of children, adolescents, or both, except when these populations were included in studies on nonoccupational postexposure prophylaxis after sexual assault. We selected studies on the effect of ART on HIV transmission among serodiscordant couples if this was a primary aim of the study and on the basis of the studys sample size. We selected population-level epidemiology studies of the effect of ART on HIV transmission if their study designs included sufficient power to determine statistical significance. We chose publications on animal models of postexposure prophylaxis and preexposure prophylaxis for scientific rigor and for the mode of HIV exposure most closely assimilating sexual HIV exposure in humans. We selected publications of observational studies on nonoccupational postexposure prophylaxis if they evaluated at least 1 of the following outcomes: 1) seroconversions, 2) adherence, 3) repeated treatment requests, or 4) effect on behavioral disinhibition. The Table summarizes these publications (615). We excluded solely descriptive articles on the uptake and prescribing practices of nonoccupational postexposure prophylaxis and articles of cost-effectiveness, ethics, policy, and case reports, except for 1 study describing a failure of nonoccupational postexposure prophylaxis. We reviewed all modeling studies but included only a few representative examples because recent studies use similar methods and differ primarily on the basis of data assumptions, as discussed. Table. Studies on Antiretroviral Nonoccupational Postexposure Prophylaxis* Using ART to Reduce Infectiousness Researchers have extensively studied the probability of sexual transmission of HIV (16). Transmission of HIV depends on the infectiousness of the host and the susceptibility of the sexual partner. Sexual transmission of HIV has been most closely linked to blood viral burden in the infected host (17, 18), which probably serves as a surrogate for HIV concentration in the genital tract (19). In a landmark study (18) of 415 serodiscordant couples conducted in Uganda, the probability of HIV transmission increased directly with blood HIV RNA concentrations. Increased transmission was not observed when HIV RNA level was less than 1500 copies/mL (18). Other studies confirm this observation (20, 21). In addition, a disproportionate number of incident cases of HIV occur with acute or early infection (22), probably because of the high viral burden associated with this stage of infection (23). Researchers have demonstrated increased genital tract shedding of HIV-1 during acute HIV infection (23, 24) and with concurrent sexually transmitted infections (2527). Antiretroviral therapy can be expected to reduce HIV RNA concentrations in blood and seminal plasma (28), female genital tract secretions (29), and rectal secretions (30). Therefore, by extension, ART would be expected to reduce infectiousness when used for treatment. However, the success of such therapy depends on the sensitivity of the virus to the agents selected, patient adherence, and the patients long-term commitment to therapy. Although some studies have shown durable longitudinal suppression of HIV (28, 31), others have demonstrated breakthrough genital tract HIV shedding (32). In addition, the magnitude of HIV suppression can be expected to reflect the differential penetration of antiviral agents into the male and female genital tracts. Accordingly, large differences between the pharmacology of antiretroviral agents in the male and female genital tracts deserve special attention (Figure 1) (31, 3341). Figure 1. Antiretroviral drug concentrations in the male and female genital tract relative to blood plasma concentrations (ratio of genital to blood plasma concentrations). Data from references 31 and 33 to 41. 3TC = lamivudine; ABC = abacavir; APV = amprenavir; ATV = atazanavir; d4T = stavudine; ddI = didanosine; DLV = delavirdine; EFV = efavirenz; ENF = enfuvirtide; FI = fusion inhibitor; FTC = emtricitabine; IDV = indinavir; LPV = lopinavir; ND = not detected; NFV = nelfinavir; NNRTI = nonnucleoside reverse transcriptase inhibitor; N(t)RTI = nucleotide reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RTV = ritonavir; SQV = saquinavir; TDF = tenofovir; ZDV = zidovudine. Penetration of antiviral agents into genital tract secretions is dictated by the degree of protein binding and by a drugs affinity for albumin and 1-acid glycoprotein. Highly protein-bound drugs (>80%) are recovered in lower concentrations in genital tract secretions compared with those in blood plasma. For example, male and female genital tract concentrations of protease inhibitors, with the exception of indinavir, are less than 10% and 50% of blood plasma, respectively. The limited penetration of protease inhibitors into the genital tract probably explains earlier reports of protease resistance in HIV isolates from seminal plasma and vaginal lavage fluid (33, 42, 43). Conversely, most nucleoside and nucleotide reverse transcriptase inhibitors, which have limited protein binding, attain genital tract concentrations that are 2- to 6-fold greater than plasma concentrations (Figure 1) (31, 3341). In addition, the active component of the nucleosides and nucleotides is the phosphorylated intracellular form and not the parent drug routinely measured. Data are available for the levels of intracellular phosphorylated forms of tenofovir, zidovudine, and lamivudine in mononuclear cells isolated from the male genital tract (34, 35). Intracellular tenofovir diphosphate concentrations are 5 to 10 times higher in male genital tract mononuclear cells than in peripheral blood mononuclear cells, whereas lamivudine triphosphate concentrations are similar to peripheral blood mononuclear cell concentrations. Zidovudine triphosphate concentrations are approximately 50% of peripheral blood mononuclear cell concentrations. The critical question is, of course, whether therapy that effectively suppresses HIV replication in the genital tract will prevent sexual transmission of HIV. To date, 2 lines of evidence have been explored to study this question: retrospective and prospective evaluation of HIV transmission in serodiscordant couples and population-level epidemiology studies. Musicco and colleagues (44) studied HIV transmission in 436 serodiscordant couples. A few men (15%) with more advanced disease took zidovudine and had a decrease in the relative risk for HIV transmission to a female sexual partner (odds ratio, 0.5 [95% CI, 0.1 to 0.9]). Castilla and colleagues (45) evaluated HIV transmission in 393 couples during prehighly active antiretroviral therapy (HAART), early HAART, and post-HAART periods (1991 to 2002) and observed an 80% reduction in HIV transmission after introduction of HAART (odds ratio, 0.14 [CI, 0.03 to 0.66]). More recently, Kayitenkore and colleagues (46) reported on HIV transmission in a cohort of 1034 serodiscordant couples from Zambia and Rwanda. In 248 couples, index partners received ART because CD4+ T-cell counts were less than 0.200109 cells/L. Only 2 of 42 partners who acquired HIV infection since 2003 had an HIV-positive partner who received ART. This is fewer than that occurring in the rest of the cohort (odds ratio, 0.19 [C

Penetration of Tenofovir and Emtricitabine in Mucosal Tissues: Implications for Prevention of HIV-1 Transmission

Antiretroviral drugs are found at different concentrations in human cervical, vaginal, and rectal mucosal tissues with implications for designing PrEP trials to prevent HIV transmission. HAARTening News for HIV Prevention Antiretroviral drug therapy (ART) has been used successfully for treating HIV-1. However, HIV transmission, principally through sexual intercourse, is still a major problem, with 7000 new infections reported daily worldwide. ART is now being investigated as a way not only to treat individuals with HIV but also to prevent the transmission of HIV infection. This strategy, called PrEP, or PrEP, requires that the concentrations of the antiretroviral drugs under investigation are at high enough concentrations in the target mucosal tissues, predominantly genital and colorectal, to prevent HIV infection. Such knowledge will be essential for designing new HIV prevention trials and also for interpreting the data from several prevention trials that have yielded conflicting results. In a new study, Patterson et al. set out to obtain this information for two antiretroviral drugs that have shown promise for HIV prevention: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). The researchers gave 12 healthy men and women a single oral dose of the fixed-dose combination pill TDF/FTC (Truvada) and then took samples of blood plasma, genital secretions, and vaginal, cervical, and rectal tissue biopsies over the next 14 days. The pro-drug forms TFV and FTC were measured in blood plasma and genital secretions, whereas the active intracellular phosphorylated metabolites of these drugs (TFV-DP and FTC-TP) were measured in vaginal, cervical, and rectal tissues. After a single oral dose, TFV and FTC were detected in blood plasma for the 14-day duration of the study. Encouragingly, the concentration of FTC was 27-fold greater in genital secretions than in blood plasma. However, the concentration of TFV was only 2.5-fold greater in genital secretions than in blood plasma. Both TFV and its active phosphorylated form TFV-DP were detected in rectal tissue for 14 days after dosing, and the cumulative exposure of rectal tissue to TFV-DP was 100-fold greater than that in vaginal and cervical tissues. In contrast, the cumulative exposure of vaginal and cervical tissues to FTC was only 10- to 15-fold greater than that for rectal tissue. Despite high concentrations of the pro-drug FTC in vaginal and cervical tissues, its active form FTC-TP was detected for ≤2 days in these tissues. This study demonstrates that the penetration of different human mucosal tissues and their exposure to the pro-drugs TFV and FTC and their active metabolites TFV-DP and FTC-TP is wide ranging and dependent on the tissue type. These findings reinforce the fact that the success of PrEP will depend on selecting the correct ART that achieves a critical concentration and duration of exposure in vulnerable mucosal tissues. Continuing pharmacological investigations will be crucial for ensuring the success of PrEP and ultimately for preventing HIV transmission. A mainstay of strategies to prevent HIV-1 transmission is to use antiretroviral therapy (ART) for pre-exposure prophylaxis (PrEP). Critical to the design and interpretation of PrEP prevention trials is the ability to make accurate pharmacological measurements of ART drugs in human genital and colorectal mucosal tissues, the principal route of HIV transmission. Here, we evaluated two drugs that are preferentially used for PrEP: tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC). A single oral dose of TDF/FTC (Truvada) was administered to 15 healthy individuals. Over the next 14 days, TFV and FTC were measured in blood plasma and genital secretions using a sensitive assay (lower level of quantification, 0.1 ng/ml). The active intracellular phosphorylated metabolites of these drugs [TFV diphospate (TFV-DP) and FTC triphosphate (FTC-TP)] were measured in homogenates prepared from rectal, vaginal, and cervical tissues. TFV and FTC were detected in blood plasma 14 days after administration of a single dose. The area under the concentration-time curve from 24 hours to 14 days (AUC1–14d) for FTC in genital secretions was 27-fold greater than in blood plasma, whereas the AUC1–14d for TFV was only 2.5-fold greater in genital secretions than in blood plasma. In rectal tissue, TFV and TFV-DP concentrations were detectable for 14 days and were 100-fold higher than the concentrations in vaginal and cervical tissues. Vaginal and cervical tissue concentrations of FTC were 10- to 15-fold higher than in rectal tissue. Despite high concentrations of FTC in vaginal and cervical tissue, FTC-TP concentrations in all tissue types were detected for only 2 days after dose. The exposure to TFV, TFV-DP, FTC, and FTC-TP was wide ranging depending on the type of mucosal tissue. These results demonstrate the need for detailed pharmacological studies to improve the application of ART for PrEP to prevent transmission of HIV.

An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients

The possibility of HIV-1 eradication has been limited by the existence of latently infected cellular reservoirs. Studies to examine control of HIV latency and potential reactivation have been hindered by the small numbers of latently infected cells found in vivo. Major conceptual leaps have been facilitated by the use of latently infected T cell lines and primary cells. However, notable differences exist among cell model systems. Furthermore, screening efforts in specific cell models have identified drug candidates for “anti-latency” therapy, which often fail to reactivate HIV uniformly across different models. Therefore, the activity of a given drug candidate, demonstrated in a particular cellular model, cannot reliably predict its activity in other cell model systems or in infected patient cells, tested ex vivo. This situation represents a critical knowledge gap that adversely affects our ability to identify promising treatment compounds and hinders the advancement of drug testing into relevant animal models and clinical trials. To begin to understand the biological characteristics that are inherent to each HIV-1 latency model, we compared the response properties of five primary T cell models, four J-Lat cell models and those obtained with a viral outgrowth assay using patient-derived infected cells. A panel of thirteen stimuli that are known to reactivate HIV by defined mechanisms of action was selected and tested in parallel in all models. Our results indicate that no single in vitro cell model alone is able to capture accurately the ex vivo response characteristics of latently infected T cells from patients. Most cell models demonstrated that sensitivity to HIV reactivation was skewed toward or against specific drug classes. Protein kinase C agonists and PHA reactivated latent HIV uniformly across models, although drugs in most other classes did not.

Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV prevention in women.

The early closure of a clinical trial assessing the effectiveness of oral antiretroviral pre-exposure prophylaxis (PrEP) in women, FEM-PrEP,1 is a substantial setback for HIV prevention. Expectations of this trial were high in view of favourable results from the pre-exposure prophylaxis initiative (iPrEX) trial,2 which studied the same drug and dosing strategy in men who have sex with men, and the Centre for the AIDS Programme of Research in South Africa (CAPRISA 004) trial,3 which tested tenofovir gel (a topical PrEP formulation) in heterosexual women. As a result, the interim FEM-PrEP trial results, announced on April 18, 2011, which showed no protection against HIV infection,1 were disappointing. Using publicly available information1 and data from other PrEP studies, we offer a potential explanation for the results of the FEM-PrEP trial.

Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis

Objectives:To describe first dose and steady state antiretroviral drug exposure in the female genital tract. Design:Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women. Method:Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA). Results:For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%). Conclusions:This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.

HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.

BACKGROUND A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge. METHODS Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed. RESULTS VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged. CONCLUSIONS Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.

Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers

Objective: The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF). Design: Open-label, multiple-dose, pharmacokinetic study in healthy volunteers. Methods: Subjects (n = 14) simultaneously received PO WARF 10 mg, vitamin K 10 mg, OMP 40 mg, CAF 2 mg/kg, and IV MDZ 0.025 mg/kg on days (D) 1 and 14, and PO MDZ 5 mg on D2 and D15. LPV/r (400/100 mg twice daily) was administered on D4-17. CYP2C9 and CYP2C19 activities were quantified by S-WARF AUC0-inf and OMP/5-hydroxy OMP ratio, respectively. CYP1A2, NAT-2, and XO activities were quantified by urinary CAF metabolite ratios. Hepatic and intestinal + hepatic CYP3A activities were quantified by IV (CL) and PO (CL/F) MDZ clearance, respectively. Results: After LPV/r therapy, CYP2C9, CYP2C19, and CYP1A2 activity increased by 29%, 100%, and 43% (P = 0.001, 0.046, and 0.001), respectively. No changes were seen in NAT-2 or XO activity. Hepatic and intestinal + hepatic CYP3A activity decreased by 77% (P < 0.001) and 92% (P = 0.001), respectively. Conclusion: LPV/r therapy results in modest induction of CYP1A2 and CYP2C9 and potent induction of CYP2C19 activity. Increasing doses of concomitant medications metabolized by these enzymes may be necessary. LPV/r inhibited intestinal CYP3A to a greater extent than hepatic CYP3A activity. Doses of concomitant CYP3A substrates should be reduced when combined with LPV/r, although intravenously administered compounds may require less of a relative dose reduction than orally administered compounds.

Physiological Changes During the Menstrual Cycle and Their Effects on the Pharmacokinetics and Pharmacodynamics of Drugs

There is an increasing awareness that the exclusion of women from clinical trials may lead to inaccurate application of drug therapy in women. Gender and estrus cycle differences in the pharmacokinetics and pharmacodynamics of drugs in animals have been appreciated for over 60 years, but investigation into these differences in humans has only recently occurred.It is postulated that hormonal fluctuations within the menstrual cycle phase may be a primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs. Existing data suggest that menstrual cycle variations do occur in renal, cardiovascular, haematological and immune systems. These physiological changes could potentially impact on the pharmacokinetics or pharmacodynamics of drugs by altering properties, such as protein binding or the volume of distribution, and thereby causing significant effects at various times during the menstrual cycle. However, systematic investigations of physiological variability throughout the menstrual cycle are limited.Fluctuations in symptom severity and clinical course coinciding with the menstrual cycle phase have been seen in some diseases. Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation. They may also worsen disease severity by impacting on the pharmacokinetics or pharmacodynamics of the medication.Menstrual cycle hormonal changes may influence drug absorption, distribution, metabolism or excretion. In vivo data to demonstrate an effect of endogenous estrogen or progesterone on pharmacokinetics are limited and contradictory.Systematic investigations of specific pharmacokinetic and pharmacodynamic changes within the menstrual cycle are lacking. Most published studies have been conducted with small numbers of women and a limited numbers of menstrual cycle phases within 1 menstrual cycle. These design problems have resulted in incomplete data for assessing the effects of the menstrual cycle. To date, there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs. With respect to drug metabolism, data are exceedingly sparse and have been collected in a suboptimal fashion. Standardisation of study design and analyses in systematic investigations of the influence of the menstrual cycle on drug pharmacokinetics and pharmacodynamics are needed.