Pharmacokinetics of long-acting lenacapavir in participants with hepatic or renal impairment.

Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.

Confirmation of the drug-drug interaction potential between cobicistat-boosted antiretroviral regimens and hormonal contraceptives.

BACKGROUND: Cobicistat (COBI), a CYP3A inhibitor, is a pharmacokinetic enhancer that increases exposures of the HIV protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV). The potential drug interaction between COBI-boosted PIs and hormonal contraceptives, which are substrates of intestinal efflux transporters and extensively metabolized by CYP enzymes, glucuronidation and sulfation, was evaluated. METHODS: This was a Phase I, open-label, two cohort (n=18/cohort), fixed-sequence study in healthy females that evaluated the drug-drug interaction (DDI) between multiple-dose ATV+COBI or DRV+COBI and single-dose drospirenone/ethinyl estradiol (EE). DDIs were evaluated using 90% confidence intervals of the geometric least-squares mean ratios of the test (drospirenone/EE+boosted PI) versus reference (drospirenone/EE) using lack of DDI boundaries of 70-143%. Safety was assessed throughout the study. RESULTS: 29/36 participants completed the study. Relative to drospirenone/EE alone, drospirenone area under the plasma concentration versus time curve extrapolated to infinity (AUCinf) was 1.6-fold and 2.3-fold higher, and maximum observed plasma concentration (Cmax) was unaltered, upon coadministration with DRV+COBI and ATV+COBI, respectively. EE AUCinf decreased 30% with drospirenone/EE + DRV+COBI and was unchanged with ATV+COBI + drospirenone/EE, relative to drospirenone/EE alone. Study treatments were generally well tolerated. The majority of adverse events were mild and consistent with known safety profiles of the compounds. CONCLUSIONS: Consistent with COBI-mediated CYP3A inhibition, drospirenone exposure increased following coadministration with COBI-containing regimens, with a greater increase with ATV+COBI. Thus, clinical monitoring for drospirenone-associated hyperkalaemia is recommended with DRV+COBI and ATV+COBI should not be used with drospirenone. Lower EE exposure with DRV+COBI may be attributed to inductive effects of DRV on CYP enzymes and/or intestinal efflux transporters (that is, P-gp) involved in EE disposition.

Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV.

OBJECTIVE: This study evaluated the relative bioavailability and pharmacokinetics of elvitegravir (EVG), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and a investigational pharmacoenhancer, cobicistat (GS-9350, COBI) coformulated as a fixed-dose combination tablet (FDC) compared with ritonavir-boosted EVG and FTC + TDF in healthy subjects. METHODS: Subjects were randomized to 1 of 2 sequences. All treatments were administered in the morning for 10 days with food, separated by a 2-day washout. Blood samples were collected over 24 hours with the last dose of each treatment. RESULTS: Forty-four subjects enrolled, 42 subjects completed all periods. All study treatments were generally well tolerated. Relative to ritonavir-boosted EVG, the geometric least-squares means ratios (GMR) [90% confidence interval (CI)] for EVG area under plasma concentration-time curve from time zero until the end of the dosing interval (AUC)tau, maximum concentration (Cmax), and trough concentration (Ctau) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150 mg/FTC/TDF. Relative to FTC + TDF, FTC GMR, and 90% CI were 127 (115 to 140) for AUCtau, 121 (107 to 137) for Cmax, and 126 (118 to 136) for Ctau; tenofovir (TFV) GMR and 90% CI were 118 (114 to 122), 130 (122 to 138), and 124 (119 to 129) for AUCtau, Cmax, and Ctau, respectively, with EVG/COBI 150 mg/FTC/TDF. CONCLUSIONS: Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG Ctau concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.

Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc.

BACKGROUND: The pharmacokinetic (PK) interaction between ritonavir-boosted elvitegravir (elvitegravir/r) and maraviroc was evaluated. METHODS: Healthy subjects were randomized to receive elvitegravir/r (150/100 mg once daily) before or after elvitegravir/r plus maraviroc (150 mg twice daily) (group 1; n = 20) or receive maraviroc before or after maraviroc plus elvitegravir/r (group 2; n = 16). All regimens were administered for 10 days and elvitegravir, ritonavir, and maraviroc PK determined. Lack of PK alteration was defined as 90% confidence intervals for ratio of geometric least squares means ratio (coadministration:alone) between 70% and 143% for elvitegravir and ritonavir Cmax (maximum concentration), Ctau (trough), and AUCtau (area under plasma concentration-time curve; 0-24 hours); for maraviroc, given a 100% increase in Cmax and AUCtau (0-12 hours); the predicted 90% confidence intervals were 162% to 247% and 136% to 295%, respectively. RESULTS: Twenty-eight of 36 enrolled subjects completed the study; one discontinuation was due to an adverse event. The most common adverse event across treatments was headache. Upon coadministration, elvitegravir and ritonavir PK were unaltered, but maraviroc exposures were 2-fold to 4-fold higher presumably due to ritonavir-mediated CYP3A-/Pgp inhibition. CONCLUSIONS: During elvitegravir/r plus maraviroc administration, no elvitegravir or ritonavir dose change and a reduced 150-mg dose of maraviroc are recommended.

Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine.

BACKGROUND: This crossover, open-label clinical study evaluated the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (elvitegravir/r), an HIV integrase inhibitor, and etravirine, a non-nucleoside reverse transcriptase inhibitor. METHODS: Healthy volunteers were randomized into one of two groups, each with two arms. Group 1 (n = 20) followed a sequence of 10-day dosing of elvitegravir/r (150/100 mg once daily) and elvitegravir/r plus etravirine (200 mg twice daily) or the reverse (n = 10 per sequence). Group 2 (n = 14) followed a sequence of 10-day dosing of etravirine and etravirine plus elvitegravir/r or the reverse (n = 7 per sequence), all under fed conditions. Elvitegravir, ritonavir and etravirine pharmacokinetics were determined on days 10 and 20 using non-compartmental analyses. Lack of pharmacokinetic alteration bounds for 90% confidence intervals (CI) about the geometric mean ratio (GMR; coadministration versus alone) were 70-143% for elvitegravir and ritonavir pharmacokinetics (maximum concentration [C(max)], concentration at the end of the dosing interval [C(tau)] and area under the plasma concentration-time curve [AUC(tau); 0-24 h] and 80-125% for etravirine pharmacokinetics (AUC(tau) 0-12 h). RESULTS: Of the 34 enrolled participants, 31 completed the study. There were three discontinuations, but none were caused by adverse events (AEs). The most common treatment-emergent AE was headache. Elvitegravir pharmacokinetic GMR was 6-7% higher following elvitegravir/r plus etravirine dosing versus elvitegravir/r. The GMR for etravirine and ritonavir AUC(tau) were 2.4% and 12.3% lower, respectively. Importantly, the 90% CI for elvitegravir and etravirine pharmacokinetics and AUC(tau) and C(max) for ritonavir were within the lack of alteration bounds. CONCLUSIONS: Elvitegravir/r and etravirine do not undergo clinically relevant drug interactions and can be coadministered without dose adjustment.

An evaluation of the process of curriculum adaptation and implementation of the problem-based learning curriculum at the Faculty of Medical Sciences, The University of the West indies, St. Augustine

This study examines the best practice in medicine and proposes a medical education programme to produce best practice doctors. This curriculum is compared to the curriculum in the Phase 1 of the Medical School in the Faculty of Medical Sciences. The name change was due to the inclusion of Dental and Veterinary Schools and later a School of Pharmacy in the faculty. This study examines the features of best practice in medicine and develops a curriculum for producing best practice doctors. The Problem-based Learning curriculum at McMaster and Maastricht is examine to determine, the extent to which the curriculum at Mt. Hope is an adaptation of these Problem-Based Learning curricula and the factors influencing the changes made. It evaluates: (1) the process of implementation of the new curriculum to determine the extent to which the principles of implementation were followed; (2) the extent to which the staff accepted and used the PBL curriculum; (3) the achievements of the students to determine the extent to which the adapted curriculum has achieved its objectives. The study also examines the deficiencies identified in the new curriculum and the attempts made to overcome these deficiencies. The results indicated that the curriculum at Mt Hope compares favorably with a best practice curriculum although there are areas that need to be included. The Mt. Hope curriculum is a hybrid PBL which has become institutionalized. It contains adaptations from both McMaster and Maastricht curricula. The planners of the Mt. Hope curriculum without formal knowledge of the process of implementation followed the entire process suggesting that there may be a situation of intuitive implementation. This is anyone implementing a curriculum will follow the same steps whether they are aware of them or not. The staff accepted PBL as a teaching strategy although their time spent in curriculum development activities was not rewarded. For the most part the curriculum was achieving its objectives while the students perceived it as being a PBL curriculum albeit a hybrid one. Both students and staff identified the steps taken to remedy them. A few deficiencies dealing with assessment still remain to be overcome. The strengths and weakness of the new curriculum were identified and recommendations made for the improvement of the curriculum. An overall assessment of the curriculum was made.

Autocatalytic RNA cleavage in the human beta-globin pre-mRNA promotes transcription termination.

New evidence indicates that termination of transcription is an important regulatory step, closely related to transcriptional interference and even transcriptional initiation. However, how this occurs is poorly understood. Recently, in vivo analysis of transcriptional termination for the human beta-globin gene revealed a new phenomenon--co-transcriptional cleavage (CoTC). This primary cleavage event within beta-globin pre-messenger RNA, downstream of the poly(A) site, is critical for efficient transcriptional termination by RNA polymerase II. Here we show that the CoTC process in the human beta-globin gene involves an RNA self-cleaving activity. We characterize the autocatalytic core of the CoTC ribozyme and show its functional role in efficient termination in vivo. The identified core CoTC is highly conserved in the 3' flanking regions of other primate beta-globin genes. Functionally, it resembles the 3' processive, self-cleaving ribozymes described for the protein-encoding genes from the myxomycetes Didymium iridis and Physarum polycephalum, indicating evolutionary conservation of this molecular process. We predict that regulated autocatalytic cleavage elements within pre-mRNAs may be a general phenomenon and that functionally it may provide the entry point for exonucleases involved in mRNA maturation, turnover and, in particular, transcriptional termination.

Utility of activated partial thromboplastin time waveform analysis for identification of sepsis and overt disseminated intravascular coagulation in patients admitted to a surgical intensive care unit.

OBJECTIVE: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described in association with overt disseminated intravascular coagulation. This abnormality, a biphasic waveform, is caused by the in vitro formation of Ca2+-induced complexes between very low density lipoprotein and C-reactive protein. We have evaluated the diagnostic utility of aPTT waveform analysis for identifying patients with overt disseminated intravascular coagulation and sepsis. DESIGN: Observational study investigating the predictive value of biphasic waveform for the diagnosis of sepsis and overt disseminated intravascular coagulation. SETTING: Surgical intensive care unit of a university hospital. SUBJECTS: We studied 331 consecutive patients admitted to the intensive care unit during a period of 6 months. INTERVENTIONS: Laboratory analyses, including prothrombin time, aPTT, aPTT waveform analysis, fibrinogen, D-dimer antigen, and platelet count. MEASUREMENTS AND MAIN RESULTS: At the most sensitive threshold value of the waveform variable for detection of the biphasic waveform (slope_1 = -0.05 %T/sec), this abnormality was detected in 54 of 331 patients (16.3%) at admission and 95 of 331 patients (28.7%) during the entire course of intensive care unit treatment. At this threshold, 59.3% of patients with a biphasic waveform on admission and 45.3% with a biphasic waveform during the total intensive care unit course were diagnosed with sepsis. Depending on the threshold value of slope_1, the sensitivity of aPTT waveform analysis for detection of sepsis varied between 22% and 55% at admission and between 48% and 74% during the entire intensive care unit stay. The specificity for sepsis varied between 92% and 98% and between 81% and 94%, for admission and total intensive care unit course, respectively. Biphasic waveform showed a comparable specificity for the diagnosis of overt disseminated intravascular coagulation, albeit at a lower sensitivity. CONCLUSIONS: As an adjunct to routine coagulation testing in intensive care unit patients, aPTT waveform analysis is an elegant means for the rapid and highly specific identification of patients with sepsis.

Using a modified course experience questionnaire (CEQ) to evaluate the innovative teaching of medical communication skills.

SETTING: At the Faculty of Medical Sciences, The University of the West Indies, St Augustine first-year students take two courses in health communication. In the Centre for Medical Sciences Education students completed a course experience questionnaire. This instrument is potentially useful in evaluating innovative programmes and securing support for their development. CONTEXT: The Faculty of Medical Sciences, The University of the West Indies, St Augustine was the first of three campuses to introduce compulsory health communication courses in 1995. Using a modified form of the 25-item course experience questionnaire (CEQ25) (Broomfield & Bligh, 1998) normally employed in overall degree or course evaluation, this study developed a 30-item questionnaire (CEQ30) to test its applicability to the evaluation of medical communication skills teaching MEASURES: In 1997 - 1998 medical, dentistry, veterinary medicine and pharmacy students completed the original short form of the CEQ25 including five items specific to medical communication skills teaching. Students used a five-point Likert scale ranging from one, indicating that they strongly disagreed with the statement, to a score of five, reporting that they strongly agreed with the statement. Principal Components Analysis with Varimax rotation analysed the scale structure of the evaluation tool. RESULTS: The principal components factor analysis of responses (n = 165) broadly confirmed five of Broomfield and Bligh's six factors, but identified a sixth factor in their original instrument (appropriate assessment) that split into two, and a seventh factor, use of available materials and resources. CONCLUSION: The modified CEQ30 is a reliable instrument with which to evaluate a course in medical communication skills, and encourage reflection on teaching and course design. Its use is applicable to medical courses during overall curriculum change and innovation in a medical school.

An evaluation of problem-based learning at Mt. Hope: Vol.1: Analysis of four aspects of the Problem-based Learning in the class of '94

This report has been produced to give the Faculty an idea of the performance of the class of 1994 in Problem-based learning in the Phase I of their programme. Four aspects of activities related to problem based learning have been analysed and some discussion and suggestions for the future.

An evaluation of problem-based learning at Mt. Hope: Vol.1: Analysis of four aspects of the Problem-based Learning in the class of '94

This report has been produced to give the Faculty an idea of the performance of the class of 1994 in Problem-based learning in the Phase I of their programme. Four aspects of activities related to problem based learning have been analysed and some discussion and suggestions for the future. (AU)