Pharmacokinetics, safety and tolerability of long-acting parenteral intramuscular injection formulations of doravirine.

WHAT IS KNOWN AND OBJECTIVE: Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection. METHODS: After confirmation of tolerability and safety of oral doravirine, 36 participants were randomized 1:1:1 to receive IM doravirine 200 mg as Treatment A (1 × 1 mL, 20% [200 mg/mL] suspension), B (1 × 0.66 mL, 30% [300 mg/mL] suspension) or C (2 × 0.5 mL, 20% suspension). Blood samples were taken as venous plasma, venous dried blood spots (DBS) and fingerstick DBS. RESULTS AND DISCUSSION: Plasma concentration-time profiles following IM treatments demonstrated rapid initial doravirine release, with initial peak ~4 days post-injection, followed by decline over the next ~6 days; a second peak was reached at ~24-36 days, corresponding to prolonged and sustained release, with measurable concentrations up to Day 183. Treatment C was associated with highest peak concentrations and shortest time to maximum concentration. Elimination half-lives for all IM formulations were prolonged versus oral administration (~46-58 days vs ~11-15 hours). Oral doravirine and IM doravirine were generally well tolerated; injection-site pain was the most common adverse event for IM doravirine. Doravirine concentrations from DBS samples showed strong correlations to venous plasma concentrations. WHAT IS NEW AND CONCLUSIONS: Novel doravirine LAP IM injection formulations investigated in this study demonstrated sustained plasma doravirine concentrations over a course of >20 weeks.

Comparative Bioavailability of Oral Granule Formulations of the HIV Antiretroviral Drugs Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate.

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.

On the Use of Group Sequential Study Designs for the Test of Bioequivalence for Complicated Products.

A novel modeling approach together with a use of group sequential study design for a complicated triple fixed-dose combination was attempted. Probability of success (POS) was used for determining a weighted average power, where weight was based on available information such as data from previous pilot studies or literature. A simulation study was conducted that resulted in the development of the necessary sample size for the studies in addition to identifying a decision algorithm that was prospectively defined in the protocols. Prospective inclusion of decision algorithms in the respective protocols facilitated a decision analytic approach to continuance or discontinuance of the product concept. Whereas the data suggested going to stage 2 was appropriate, the overall POS of meeting the equivalence requirements upon completion of the study were very low, leading to termination of the selected formulation concepts. The use of such novel designs for bioequivalence assessment can be applied for staged investments, particularly when there is uncertainty in formulation POS or when the pilot-scale pharmacokinetic studies are not likely to predict the final-scale pivotal studies.

The Effect of Food on Doravirine Bioavailability: Results from Two Pharmacokinetic Studies in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Doravirine is a novel non-nucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1. In two open-label, single-dose, randomized, two-period, crossover trials, the bioavailability of doravirine administered alone or in a fixed-dose combination (FDC) was determined under fed and fasted conditions. METHODS: Doravirine 100 mg alone or with lamivudine and tenofovir disoproxil fumarate (each 300 mg) were administered to healthy subjects fasted or 30 min after a high-fat, high-calorie breakfast. Twenty-eight subjects, aged 26-55 years, enrolled (doravirine, n = 14; FDC, n = 14). The sequence of fed/fasted treatment was randomized (1:1). Pharmacokinetic data were analyzed as geometric mean ratios (GMRs) with 90% confidence intervals. RESULTS: Doravirine area under the plasma concentration-time curve (AUC) from time zero to infinity (fed/fasted GMRs: alone 1.16 [1.06-1.26]; FDC 1.10 [1.02-1.20]), AUC from time zero to the last measurement (GMRs: alone 1.18 [1.08-1.29]; FDC 1.10 [1.01-1.20]), and plasma concentration 24 h after administration (GMRs: alone 1.36 [1.19-1.55]; FDC 1.26 [1.13-1.41]) values increased in the fed versus fasted state when administered alone or as the FDC; the magnitude was not clinically meaningful. Doravirine maximum achieved concentration was similar after fed or fasted administration for both doravirine alone and FDC (GMRs: alone 1.03 [0.89-1.19]; FDC 0.95 [0.80-1.12]). The pharmacokinetics of tenofovir and lamivudine in the FDC were also slightly altered by administration with food; the changes were not clinically meaningful. CONCLUSIONS: All treatments were generally well tolerated. Food had no clinically meaningful effect on doravirine 100 mg alone or as part of an FDC.

Effect of gender and age on the relative bioavailability of doravirine: results of a Phase I trial in healthy subjects.

BACKGROUND: Doravirine is a potent, once-daily, non-nucleoside reverse transcriptase inhibitor with a distinct resistance profile in Phase III development for the treatment of HIV-1. As doravirine may be administered to women and the elderly, we investigated the effect of gender and age in doravirine pharmacokinetics. METHODS: In this Phase I, open-label, single-period, parallel-group investigation, doravirine 100 mg was administered to 36 healthy subjects in three groups: elderly men (n=12, 65-80 years), elderly women (n=12, 65-80 years) and young women (n=12, 18-50 years). Data for young men (n=6, 18-50 years) from a previous study were included as a comparator. Doravirine plasma pharmacokinetics and safety were assessed. RESULTS: No clinically meaningful effect on pharmacokinetics was observed in association with gender or age. Gender effects were assessed using combined data from elderly and young men versus elderly and young women because the datasets met predefined pooling criteria. The geometric mean ratios (GMRs; women/men [90% CIs]) of doravirine AUC0-∞, Cmax and C24h were 1.20 (1.03, 1.40), 1.42 (1.23, 1.64) and 1.02 (0.84, 1.24), respectively. Age effects were assessed separately in men and women because the datasets did not meet pooling criteria. The AUC0-∞, Cmax, and C24h GMRs (elderly/young) were 0.85 (0.67, 1.10), 0.92 (0.73, 1.16), 0.81 (0.59, 1.11), respectively for men and 0.97 (0.79, 1.19), 1.18 (0.98, 1.42), 0.94 (0.72, 1.21), respectively, for women. Doravirine was well-tolerated throughout the trial. CONCLUSIONS: Neither gender nor age affects the bioavailability of single-dose doravirine 100 mg in healthy subjects, thus supporting administration of doravirine 100 mg in elderly and adult women without dose adjustment.

State-Dependent Resource Harvesting with Lagged Information about System States.

Markov decision processes (MDPs), which involve a temporal sequence of actions conditioned on the state of the managed system, are increasingly being applied in natural resource management. This study focuses on the modification of a traditional MDP to account for those cases in which an action must be chosen after a significant time lag in observing system state, but just prior to a new observation. In order to calculate an optimal decision policy under these conditions, possible actions must be conditioned on the previous observed system state and action taken. We show how to solve these problems when the state transition structure is known and when it is uncertain. Our focus is on the latter case, and we show how actions must be conditioned not only on the previous system state and action, but on the probabilities associated with alternative models of system dynamics. To demonstrate this framework, we calculated and simulated optimal, adaptive policies for MDPs with lagged states for the problem of deciding annual harvest regulations for mallards (Anas platyrhynchos) in the United States. In this particular example, changes in harvest policy induced by the use of lagged information about system state were sufficient to maintain expected management performance (e.g. population size, harvest) even in the face of an uncertain system state at the time of a decision.

Efficient use of information in adaptive management with an application to managing recreation near golden eagle nesting sites.

It is generally the case that a significant degree of uncertainty exists concerning the behavior of ecological systems. Adaptive management has been developed to address such structural uncertainty, while recognizing that decisions must be made without full knowledge of how a system behaves. This paradigm attempts to use new information that develops during the course of management to learn how the system works. To date, however, adaptive management has used a very limited information set to characterize the learning that is possible. This paper uses an extension of the Partial Observable Markov Decision Process (POMDP) framework to expand the information set used to update belief in competing models. This feature can potentially increase the speed of learning through adaptive management, and lead to better management in the future. We apply this framework to a case study wherein interest lies in managing recreational restrictions around golden eagle (Aquila chrysaetos) nesting sites. The ultimate management objective is to maintain an abundant eagle population in Denali National Park while minimizing the regulatory burden on park visitors. In order to capture this objective, we developed a utility function that trades off expected breeding success with hiker access. Our work is relevant to the management of human activities in protected areas, but more generally demonstrates some of the benefits of POMDP in the context of adaptive management.

Addressing structural and observational uncertainty in resource management.

Most natural resource management and conservation problems are plagued with high levels of uncertainties, which make good decision making difficult. Although some kinds of uncertainties are easily incorporated into decision making, two types of uncertainty present more formidable difficulties. The first, structural uncertainty, represents our imperfect knowledge about how a managed system behaves. The second, observational uncertainty, arises because the state of the system must be inferred from imperfect monitoring systems. The former type of uncertainty has been addressed in ecology using Adaptive Management (AM) and the latter using the Partially Observable Markov Decision Processes (POMDP) framework. Here we present a unifying framework that extends standard POMDPs and encompasses both standard POMDPs and AM. The approach allows any system variable to be observed or not observed and uses any relevant observed variable to update beliefs about unknown variables and parameters. This extends standard AM, which only uses realizations of the state variable to update beliefs and extends standard POMDP by allowing more general stochastic dependence among the observable variables and the state variables. This framework enables both structural and observational uncertainty to be simultaneously modeled. We illustrate the features of the extended POMDP framework with an example.

The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR-1 Antagonist, in Healthy Adult Subjects.

In this open-label, randomized, 2-period crossover study, 16 healthy subjects received a single oral 2.5-mg dose of vorapaxar in the fed (i.e., standardized high-fat breakfast) and fasted (i.e., an overnight fast) state with a 6-week washout. Plasma samples for vorapaxar assay were obtained pre-dose and up to 72 hours post-dose. Least squares (LS) geometric mean AUC0-72 hr and Cmax were analyzed by ANOVA. If 90% confidence intervals (CI) for the geometric mean ratios (GMRs; fed/fasted) of AUC0-72 hr and Cmax were within the 50-200% range, then food was deemed not to have a clinically important effect. The LS geometric mean (90% CI) AUC0-72 hr and Cmax of vorapaxar in the fasted state were 314 (284-348) ng hr/mL and 23.4 (20.7-26.4) ng/mL, respectively. The GMRs (fed/fasted) and 90% CIs for AUC0-72 hr and Cmax were 96.9 (92.2-102) and 79.1 (67.6-92.5), respectively. Vorapaxar was generally safe and well tolerated in the presence and absence of food. Concomitant food decreased the rate (i.e., 21% reduction in Cmax and 45-min delay in Tmax ) with no effect on the extent of vorapaxar absorption when administered as a single 2.5-mg dose. Thus, vorapaxar can be administered without regard to food.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

An adaptive-management framework for optimal control of hiking near golden eagle nests in Denali National Park.

Unintended effects of recreational activities in protected areas are of growing concern. We used an adaptive-management framework to develop guidelines for optimally managing hiking activities to maintain desired levels of territory occupancy and reproductive success of Golden Eagles (Aquila chrysaetos) in Denali National Park (Alaska, U.S.A.). The management decision was to restrict human access (hikers) to particular nesting territories to reduce disturbance. The management objective was to minimize restrictions on hikers while maintaining reproductive performance of eagles above some specified level. We based our decision analysis on predictive models of site occupancy of eagles developed using a combination of expert opinion and data collected from 93 eagle territories over 20 years. The best predictive model showed that restricting human access to eagle territories had little effect on occupancy dynamics. However, when considering important sources of uncertainty in the models, including environmental stochasticity, imperfect detection of hares on which eagles prey, and model uncertainty, restricting access of territories to hikers improved eagle reproduction substantially. An adaptive management framework such as ours may help reduce uncertainty of the effects of hiking activities on Golden Eagles.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified release products: workshop summary report.

Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified-release products: workshop summary report.

Modified-release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to discuss current regulatory expectations and industry practices for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: Workshop summary report.

BACKGROUND: Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. OBJECTIVE: This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1-2, 2009, in Baltimore, Maryland. METHODS: The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical equivalence and bioequivalence of oral MR products. RESULTS: In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioequivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioequivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioequivalence limits may be set based on the known within-subject variability for the reference product. CONCLUSIONS: The current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioequivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response.

Summary workshop report: bioequivalence, biopharmaceutics classification system, and beyond.

The workshop "Bioequivalence, Biopharmaceutics Classification System, and Beyond" was held May 21-23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.