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During metabolic stress testing, 9 of 20 patients with left ventricular assist devices exhibited a lag in peak device rate by < or = 85% of peak native heart rate (group I), with peak device rates of 118 +/- 9 beats/min compared with group II, in which peak device rate nearly equaled peak native rates. Peak systolic blood pressure was significantly greater in group II than group I, but there was no significant difference in peak oxygen consumption, anaerobic threshold, or peak flows. [ABSTRACT FROM AUTHOR]

Islatravir, a deoxyadenosine analog that inhibits HIV-1 replication by multiple mechanisms of action, including reverse transcriptase translocation inhibition, is being developed for use in HIV-1 treatment. People living with HIV often have comorbidities, such as dyslipidemia or type 2 diabetes mellitus, necessitating long-term concomitant drug therapy. This nonrandomized, two-period, fixed-sequence, open-label, phase 1, drug-drug interaction study was conducted to evaluate the effects of islatravir coadministration on atorvastatin and metformin pharmacokinetics (PK) in healthy adults. In period 1, participants received a single dose of atorvastatin 20 mg and metformin 1000 mg. After a 5-day washout, participants received atorvastatin 20 mg and metformin 1000 mg coadministered with a single oral dose of islatravir 60 mg (period 2). In both periods, blood samples were collected up to 72 h post dose to characterize the plasma PK of atorvastatin and metformin. Safety was monitored throughout the study. Fourteen participants were enrolled and completed the study. Atorvastatin and metformin plasma PK were similar after administration of atorvastatin and metformin with or without islatravir. The geometric mean ratio and 90% confidence interval of the area under the concentration-time curve from time zero to infinity (AUC 0-∞ ) for atorvastatin and metformin with or without a single oral dose of islatravir were 1.04 (1.00-1.10) and 0.87 (0.79-0.96), respectively. Coadministration of islatravir with atorvastatin and metformin was well tolerated. Overall, coadministration of atorvastatin and metformin with a single oral dose of islatravir did not have a clinically meaningful effect on the PK profiles of either drug., (© 2024 Merck Sharp & Dohme LLC. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t ½ ) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t ½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t ½ of 73 hours. The t ½ (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t ½ , supporting further clinical investigation of islatravir administered at an extended dosing interval., Competing Interests: X.Z., W.A., R.V., S.A.S., M.I., and R.P.M. are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or options in Merck & Co., Inc., Rahway, NJ, USA. W.A. was an employee of Merck & Co., Inc., Rahway, NJ, USA, at the time the study was conducted. W.K.K. has no conflicts to report.

Long-acting injectable (LAI) formulations can provide several advantages over the more traditional oral formulation as drug product opportunities. LAI formulations can achieve sustained drug release for extended periods of time, which results in less frequent dosing requirements leading to higher patient adherence and more optimal therapeutic outcomes. This review article will provide an industry perspective on the development and associated challenges of long-acting injectable formulations. The LAIs described herein include polymer-based formulations, oil-based formulations, and crystalline drug suspensions. The review discusses manufacturing processes, including quality controls, considerations of the Active Pharmaceutical Ingredient (API), biopharmaceutical properties and clinical requirements pertaining to LAI technology selection, and characterization of LAIs through in vitro, in vivo and in silico approaches. Lastly, the article includes a discussion around the current lack of suitable compendial and biorelevant in vitro models for the evaluation of LAIs and its subsequent impact on LAI product development and approval., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP)., Setting: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level., Methods: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal., Results: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6  cells) were above the PK threshold for all dose levels., Conclusion: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m 2 ) and to healthy individuals without renal impairment (matched control group; eGFR ≥90 mL/min/1.73 m 2 ). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC 0-∞ ) were ~2-fold and ~5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC 0-∞ was ~1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function. (This study has been registered at ClinicalTrials.gov under registration no. NCT04303156.).

Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.

A randomized, multicenter, open-label study explored the effect of a fixed-dose (FD) of plerixafor versus the approved weight-based (WB) dose for the mobilization of hematopoietic stem cells (HSCs) in patients with non-Hodgkin's lymphoma and a body weight of ≤70 kg. After mobilization with granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/day for 4 days, patients were randomized 1:1 to either plerixafor FD 20 mg (n = 30) or WB 0.24 mg/kg (n = 31) on the evening of Day 4. Co-primary endpoints were the proportion of patients achieving ≥5 × 10 6 CD34 + cells/kg in ≤4 days of apheresis, and total systemic exposure to plerixafor (area under the concentration-time curve from 0 to 10 h [AUC 0-10 ]). There was no statistically significant difference between the proportion of patients attaining the primary efficacy endpoint (60% FD arm, 55% WB arm; P = 0.395). Exposure to plerixafor was greater in the FD arm relative to the WB arm; however, there was no appreciable difference regarding fold increases of peripheral blood CD34 + cells. The safety profile was similar between treatment groups. These results suggest there is no statistically significant difference in HSC mobilization with a standard WB dosing regimen of plerixafor plus G-CSF in patients with low body weight compared with an FD regimen.

The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin lymphoma (NHL; n = 167) and multiple myeloma (MM; n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34 + cells for autologous hematopoietic stem cell transplantation. Overall survival (OS) and progression-free survival (PFS) were evaluated over a 5-year period following the first dose of plerixafor or placebo. The probability of OS was not significantly different in patients with NHL or MM treated with plerixafor or placebo (NHL: 64%; 95% confidence interval [CI], 56% to 71% versus 56%; 95% CI, 44% to 67%, respectively; MM: 64%; 95% CI, 54% to 72% versus 64%; 95% CI, 53% to 73%, respectively). In addition, there was no statistically significant difference in the probability of PFS over 5 years between treatment groups in patients with NHL (50%; 95% CI, 44% to 67% for plerixafor versus 43%; 95% CI, 31% to 54% for placebo) or those with MM (17%; 95% CI, 10% to 24% for plerixafor versus 30%; 95% CI, 21% to 40% for placebo). In this long-term follow-up study, the addition of plerixafor to G-CSF for stem cell mobilization did not affect 5-year survival in patients with NHL or patients with MM., (Copyright © 2018. Published by Elsevier Inc.)

Objectives: Blockade of N-methyl-D-aspartate receptors containing the NR2B subunit has been shown to be therapeutic in animal models of Parkinson disease (PD). However, findings with investigational NR2B receptor antagonists in PD patients have been mixed. The objective of this study was to evaluate the effects of the NR2B selective N-methyl-D-aspartate receptor antagonist MK-0657 on levodopa-induced dyskinesias and motor symptoms in PD patients., Methods: A randomized, double-blind, single-dose, 2-period crossover study was conducted in 22 patients with PD and levodopa-induced peak-dose dyskinesias. Patients received oral MK-0657 (7 mg) or placebo, in randomized order, on each of 2 test days. On both days, levodopa was administered as a 2-hour intravenous infusion at greater than or equal to 1 mg/kg per hour with frequent assessments of dyskinesia, motor function, and pharmacokinetics., Results: MK-0657 7 mg had no significant effect on dyskinesias (difference versus placebo in modified Abnormal Involuntary Movement Scale mean change from baseline area under the curve over 5 hours, -2.3; 95% confidence interval, -5.1 to 0.4) or motor function (difference versus placebo in Unified Parkinson's Disease Rating Scale Part III mean change from baseline area under the curve over 5 hours, 13.9; 95% confidence interval, -1.7 to 29.5). MK-0657 7 mg achieved the target mean maximum plasma concentration of 400 nM., Conclusions: These data suggest that a single dose of MK-0657 7 mg is not effective in improving levodopa-induced dyskinesias and motor symptoms in PD patients., Clinical Trial Registration: clinicaltrials.gov NCT00505843.

Development of in vitro-in vivo correlations (IVIVCs) for extended-release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross-over study against immediate-release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Medical civil military operations (MCMO) are part of military civil capacity-building efforts within the full spectrum of military operations, from war to military operations other than war. In 2008-2009 during Operation Iraqi Freedom, the Division Surgeon's Section (DSS) of the 25th Infantry Division (25ID) and Multinational Division-North developed an innovative MCMO program in northern Iraq. The program centered on understanding and mapping key relationships, empowering brigade-level programs, and leveraging technology to identify and share best practices. The DSS mapped the critical relationships within and between the three entities affecting MCMO: the government of Iraq (GOI), Department of State (DOS), and the Department of Defense (DOD). A division MCMO working group was then created along with processes to facilitate MCMO project execution and program management. The structure and organization of the 25ID MCMO program lend themselves to other operational environments requiring synchronization of medical capacity-building efforts.

Background: Implantable left ventricular assist device (LVAD) insertion complicated by early right ventricular (RV) failure has a poor prognosis and is generally unpredictable., Methods: To determine preoperative risk factors for perioperative RV failure after LVAD insertion, patient characteristics and preoperative hemodynamics were analyzed in 100 patients with the HeartMate LVAD (Thermo Cardiosystems, Inc, Woburn, MA) at the Cleveland Clinic., Results: RV assist device support was required for 11 patients (RVAD group). RVAD use was significantly higher in younger patients, female patients, smaller patients, and myocarditis patients. There was no significant difference in the cardiac index, RV ejection fraction, or right atrial pressure between the two groups preoperatively. The preoperative mean pulmonary arterial pressure (PAP) and RV stroke work index (RV SWI) were significantly lower in the RVAD group (p = 0.015 and p = 0.011, respectively). Survival to transplant was poor in the RVAD group (27%) and was 83% in the no-RVAD group., Conclusions: The need for perioperative RVAD support was low, only 11%. Preoperative low PAP and low RV SWI were significant risk factors for RVAD use.

Background: Implantable left ventricular assist devices are common as a bridge to transplantation but are just reaching their goal as an alternative to transplantation., Methods: From December 1991 until December 1996, 97 left ventricular assist devices were implanted as a bridge to transplantation, one as an alternative to transplantation, and two as a bridge to recovery. Included were 64 pneumatic devices and 36 electric devices. Most patients (69%) had ischemic cardiomyopathy and most (53%) had had previous cardiac surgery. Preoperative circulatory support (extracorporeal membrane oxygenation) was used in 25., Results: Perioperative insertion of a right ventricular assist device was unusual (11%). The mean duration of support with a left ventricular assist device (bridge to transplantation) was 70 +/- 41 days (up to 206 days). Survival to transplantation was 76%. Cause of death included multiple organ failure (n = 13), perioperative stroke (n = 5), device failure (n = 5), and controller disconnect (n = 1). Significant risk factors for death included (1) preoperative need for ventilator or extracorporeal membrane oxygenation, (2) elevated blood urea nitrogen, creatinine, or bilirubin, and (3) low pulmonary artery pressures. Risks after insertion of the left ventricular assist device were reoperation for bleeding, support with a right ventricular assist device, dialysis, or device failure. Catastrophic failure of the device occurred 14 times in 12 patients and was treated by emergency pump exchange in six instances. Only two device-related thromboembolic episodes were detected. Positive blood cultures were found in 59% of patients, driveline infection in 28%, and pump infection in 11%., Conclusions: The HeartMate device provided excellent hemodynamic support with low device-related thromboembolic events. Infection and reliability of the device contributed to the high cost of therapy. These areas need to be improved for the left ventricular assist device to attain its goal as a viable alternative to transplantation.

Objective: We sought to determine the role of partial left ventriculectomy in patients with dilated cardiomyopathy., Methods: Since May 1996 we have performed partial left ventriculectomy in 53 patients, primarily (94%) in heart transplant candidates. The mean age of the patients was 53 years (range 17 to 72 years); 60% were in class IV and 40% in class III. Preoperatively, 51 patients were thought to have idiopathic dilated cardiomyopathy, one familial cardiomyopathy, and one valvular cardiomyopathy. As our experience accrued we increased the extent of left ventriculectomy and more complex mitral valve repairs. For two patients mitral valve replacement was performed. For 51 patients the anterior and posterior mitral valve leaflets were approximated (Alfieri repair); 47 patients also had ring posterior annuloplasty. In 27 patients (51%) one or both papillary muscles were divided, additional left ventricular wall was resected, and the papillary muscle heads were reimplanted., Results: Echocardiography showed a significant decrease in left ventricular dimensions after resection (8.3 cm to 5.8 cm), reduction in mitral regurgitation (2.8+ to 0), and increase in forward ejection fraction (15.7% to 32.7%). Cardiac index did not increase significantly (2.2 to 2.4 L/min per square meter). Eight patients (15%) required a perioperative left ventricular assist device; one died and was the only perioperative mortality (1.9%). At 11 months, actuarial survival was 87% and freedom from relisting for transplantation was 72%., Conclusions: Improved selection criteria are necessary to avoid early failures, and much more follow-up and analyses of data are mandatory. However, the operation may become a biologic bridge, or even alternative, to transplantation.

Background: Patients bridged to transplantation (TX) with the implantable left ventricular assist device (LVAD) may be at increased risk for the development of panel-reactive antibodies (PRA) during support., Methods: To investigate that, we evaluated 60 patients who received the HeartMate LVAD at our institution, of whom 53 had PRA results available for analysis. T lymphocyte PRA levels were examined before LVAD, at the peak PRA level during LVAD support (PEAK), and just before TX. A PRA level more than 10% was considered indicative of sensitization against HLA antigens., Results: The only factor that had a significant effect on PRA levels before LVAD was patient's sex (1.3% for men versus 7.4% for women; p = 0.005). During LVAD support, peak PRA levels increased significantly and the sex-associated differences were no longer evident (33.3% men, 34.3% women; not significant). At the time of TX, PRAs decreased to 10.9% (men) and 7.0% (women) (not significant). We examined the influence of blood products received before TX on PRA levels. Patients who received less than the median number of total units (median). When examined by the type of blood product, only the number of platelet transfusions significantly increased the peak PRA (median: 46.9%; p = 0.03). Patients who received blood that was leukocyte-depleted tended to have lower TX PRA levels (2.9%) compared with those who did not (13.9%, p = 0.18). Forty-two patients were successfully bridged to TX, with three early and two late deaths after TX. Whereas 39 patients received transplants without intervention, 3 were treated by plasmapheresis with a 77% reduction in their HLA antibody levels at TX as measured by flow cytometry., Conclusions: Patients with the implantable LVAD are at significant risk for the development of anti-HLA antibodies during support. Although this sensitization is often transient, intervention using plasmapheresis may be useful for some patients.

A 67-year-old man had end-stage ischemic cardiomyopathy. He had had two previous coronary bypass operations and a previous left ventricular aneurysmectomy. In December 1995 he underwent vented-electric HeartMate LVAD insertion as an alternative to transplantation. He was discharged from the hospital 13 days after the operation, and 5 months postoperatively he had returned to New York Heart Association functional class II.