Rosa F. Yeh

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.

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.

Full validation of an analytical method for the HIV-protease inhibitor atazanavir in combination with 8 other antiretroviral agents and its applicability to therapeutic drug monitoring

Because HIV medications are used in combination, it is important to develop multiplex assays to streamline the therapeutic drug monitoring process and provide rapid turnaround. This article reports full validation of an analytical method that combines atazanavir with 6 HIV-protease inhibitors (indinavir, amprenavir, saquinavir, nelfinavir, ritonavir, and lopinavir) and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine and efavirenz). Using 200 μL of plasma and a simple liquid–liquid extraction method, this analytical method achieved a clean baseline and high extraction efficiencies (90.0% to 99.5%). A Zorbax C-18 (150×4.6 mm, 3.5 μm) analytical column was used along with a 27-minute linear gradient elution of the mobile phase to provide sharp peaks at 210 nm. This method was validated over a range of 25 to 10,000 ng/mL and is accurate (90.4% to 110.5%) and precise (precision within a day and between days ranged from 2.3% to 8.3%). Because this method is simple and inexpensive, it may have applicability in countries with low resources.

Genital Tract, Cord Blood, and Amniotic Fluid Exposures of Seven Antiretroviral Drugs during and after Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women

ABSTRACT The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (≥100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were ≥100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were ≤6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.

Use/misuse of over-the-counter medications and associated adverse drug events among HIV-infected patients.

BACKGROUND Self-medication practices and polypharmacy are common among human immunodeficiency virus (HIV)-infected patients. Inappropriate use of over-the-counter (OTC) medications potentiates the risk for drug misuse and adverse drug events (ADEs). OBJECTIVES To investigate use and misuse of OTC medications in HIV-infected patients and determine related ADEs. METHODS A nonexperimental cross-sectional field study design was used. Study subjects were HIV-infected patients from a local HIV clinic in Houston, TX. Information on subject demographics, OTC medication use, and ADEs experienced were obtained using combined self-administered questionnaire and personal interview techniques. Misuse was divided into 3 categories: strength/frequency misuse, length misuse, and condition misuse. Data were analyzed using descriptive and Chi-square analyses. RESULTS A total of 215 completed surveys were obtained, with a net response rate of 63.6%. The mean (+/-SD) age of the respondents was 45 (+/-8.32) years and 69% were males. Analgesics/antipyretics (64.2%) were the most commonly used OTC medications of which nonsteroidal agents accounted for the greatest proportion (38.4%). Of the respondents, 80 (37.2%) misused OTC medications. The highest incidence occurred in length misuse (46.3%), followed by strength/frequency misuse (45.6%), and condition misuse (8.1%). Categories of misuse overlapped in 30 cases (20.1%). Thirty-six (16.7%) participants experienced at least one or more ADEs related to OTC medication use/misuse. Occurrence of ADEs was significantly higher in patients who misused OTC medications compared with those who did not (P < .05). CONCLUSIONS Analgesics/antipyretics were the most commonly used OTC medications by HIV-infected patients. The incidence of misuse and ADEs associated with OTC medications were documented with the sample. Keeping in mind the limitations of study design, our findings suggest that misuse of OTC medications in HIV-infected patients may increase the incidence of ADEs experienced.

Impact of Sample Size on the Performance of Multiple-Model Pharmacokinetic Simulations

ABSTRACT Monte Carlo simulations are increasingly used to predict pharmacokinetic variability of antimicrobials in a population. We investigated the sample size necessary to provide robust pharmacokinetic predictions. To obtain reasonably robust predictions, a nonparametric model derived from a sample population size of ≥50 appears to be necessary as the input information.

Symposium on roles of and cooperation between academic- and practice-based pharmacy clinicians.

PURPOSE The findings of an academic symposium as they relate to the history and role of the academic pharmacy clinician, the strengths and limitations of the academic pharmacy clinician model, and the framework for future synergistic work relations among clinical pharmacy practitioners are summarized. SUMMARY On April 23, 2008, a symposium was convened to bring key thought leaders together to discuss the relationship of the academic-based pharmacy clinician and the practice-based pharmacy clinician. Participants included clinical faculty and administrators from two colleges of pharmacy, practice-based clinical pharmacists and pharmacy managers from seven health care institutions, and representatives from the American Association of Colleges of Pharmacy, the American College of Clinical Pharmacy, and the American Society of Health-System Pharmacists. Symposium participants discussed the roles and expectations of clinical pharmacists based on primary affiliation within the contemporary practice model for academic- and practice-based pharmacy clinicians and identified sources of conflict for academic- and practice-based pharmacy clinicians. Symposium participants agreed that in order to succeed, the academic-based and the practice-based pharmacy clinicians must function in a true partnership as each individual has strengths, resources, and benefits to bring to the relationship. Furthermore, knowledge, consideration, and an understanding of the potentially different goals and objectives of each institution are critical. CONCLUSION A symposium attended by clinical faculty members and administrators from two colleges of pharmacy, practice-based clinical pharmacists and pharmacy managers from seven health care institutions, and representatives from three national pharmacy organizations was conducted to discuss the roles of and cooperation between academic- and practice-based pharmacy clinicians.

Lopinavir/ritonavir dosage form affects quality of life during monotherapy in HIV-positive adults.

This was a single-center, open-label study of lopinavir/ritonavir (LPV/r) single-agent therapy in antiretroviral-naive, HIV-infected participants initiating therapy with twice-daily soft-gelatin capsules (SGC) and switched to tablets after ≥4 weeks. The objective was to evaluate quality of life and tolerability of the 2 formulations. Participants quality of life, depression, and tolerability were measured using the Medical Outcomes Study-HIV (MOS-HIV), Modified Global Condition Improvement (GCI), and Center for Epidemiologic Studies-Depression (CES-D), prior to and 4 weeks following switch. MOS-HIV showed significant improvements in general health perception (+6 (16), mean (SD); P = .047) and role functioning (+8 (19), mean (SD); P = .023) post-switch. GCI showed significant improvement in ease of taking medications with tablets (56.7% vs 83.3%; P = .021). No change was observed in CES-D. Tolerability improved in 47%. Reported diarrhea (grade 2) was higher during SGC (33.3% vs3.3%; P = .004). Quality-of-life measures, tolerability, and diarrhea improved with the LPV/r tablet formulation compared to SGC in HIV-positive patients not receiving other antiretroviral therapy (ART).

Impact of Over-the-Counter Medication Misuse and Adverse Drug Events on HIV Patients' Health-Related Quality of Life

Background: Over-the-counter (OTC) medication use has increased among HIV-infected patients. Inappropriate use of OTC drugs may increase the risk of potential adverse drug events (ADEs), thus decreasing health-related quality of life (HRQL). Objective: To examine the effect of OTC medication misuse and associated ADEs on HRQL of HIV-infected patients. Methods: A cross-sectional field study with HIV-infected patients from an HIV clinic in Houston, Texas, was conducted from April 1, 2005, to June 30, 2005. A validated questionnaire (including questions on OTC medications used; ADEs experienced; and HRQL, Short Form-12, version 2 scale) was administered using self-administered and personal interview techniques. Cronbachs α was estimated to evaluate internal consistency for HRQL scores and χ2 and t-test analyses were performed to evaluate the effect of OTC misuse on ADEs and on HRQL. Results: Of the 215 respondents, 80 (37.2%) misused OTC medications. Thirty-six participants (16.7%) experienced ADEs due to OTC use or misuse. ADE incidence was significantly higher in patients misusing OTCs. Significantly lower HRQL scores for the physical component summary score domains were observed in patients reporting ADEs versus those who did not. Conclusions: HIV-infected patients had lower HRQL scores when they experienced an OTC-associated ADE. Patients misusing OTC medications had a higher incidence of associated ADEs. Interventions by healthcare providers and patients aimed at reducing misuse and ADEs due to OTC medications would improve care and the quality of life for HIV-infected patients.

The association of pharmacy drug-delivery services with adherence in an urban HIV population

The aim of this study was to examine the effect of drug‐distribution methods on antiretroviral medication adherence in HIV‐positive patients.