The effect of reduced gastric acid secretion on the gastrointestinal disposition of a ritonavir amorphous solid dispersion in fasted healthy volunteers: an in vivo - in vitro investigation.

This paper summarizes efforts to (i) better understand the behavior of amorphous solid dispersions (ASDs) under real-life dosing conditions and (ii) evaluate the capability of in vitro methodologies to capture gastro-intestinal drug disposition. In a first part of the study, five healthy volunteers participated in a two-way crossover trial in which one Norvir® tablet (100 mg ritonavir) was dosed under fasted and fasted + PPI conditions. Gastrointestinal aspirates were collected from both the stomach and duodenum as a function of time to map the gastrointestinal drug disposition of the ritonavir ASD formulation and to evaluate the impact of reduced gastric acid secretion on formulation performance. In both test conditions, ritonavir was shown to supersaturate in the upper GI tract illustrating the capacity of the formulation strategy itself to generate supersaturated drug content. In parallel, in vivo test conditions were closely mimicked in a multitude of in vitro methodologies (i.e., USP II dissolution apparatus, BioGIT and TIM-1 system) with the aim to evaluate their ability to predict in vivo gastrointestinal drug disposition. The selected in vitro methodologies were found capable of qualitatively and/or quantitatively picking up trends observed in the intraluminal sampling study.

Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices.

Acalabrutinib (Calquence®) 100 mg (bid) has received accelerated approval by FDA for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Acalabrutinib is a substrate of PgP and CYP3A4, with a significant fraction of drug metabolized by first pass gut extraction and 25% absolute bioavailability. The absorption of acalabrutinib is affected by stomach pH, with lower pharmacokinetic exposure observed following co-administration with proton pump inhibitors. During dissolution at pH values below its highest basic pKa, the two basic moieties of acalabrutinib react with protons from the aqueous solution, leading to a higher pH at the drug surface than in the bulk solution. A batch-specific product particle size distribution (P-PSD), was derived from dissolution data using a mechanistic model that was based on the understanding of surface pH and the contribution of micelles to the dissolution rate. P-PSD values obtained for various batches of acalabrutinib products in simple buffers, or in complex fluids such as fruit juices, were successfully integrated into a physiologically based pharmacokinetic (PBPK) model developed using GastroPlus v9.0™. The integrated model allowed the prediction of clinical pharmacokinetics under normal physiological stomach pH conditions as well as following treatment with proton pump inhibitors. The model also accounted for lower pharmacokinetic exposure that was observed when acalabrutinib was co-administered with the acidic beverages, grapefruit juice, (which contains CYP3A inhibitors), and orange drink (which does not contain CYP3A inhibitors), relative to administration with water. The integration of dissolution data in the PBPK model enables mechanistic understanding and the establishment of more robust in vitro-in vivo correlations (IVIVC) under a variety of conditions. The model can then distinguish the interplay between dissolution and first pass extraction and how in vivo stomach pH, saturation of gut PgP, and saturation or inhibition of gut CYP3A4, will impact the pharmacokinetics of acalabrutinib.

Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modelling of drug product dissolution to derive a P-PSD for PBPK model input.

Drug product dissolution for four batches of acalabrutinib 100 mg capsules were analyzed with in vitro dissolution in various pH conditions and in media containing synthetic surfactant micelles or biorelevant micelles. Non-sink conditions, where the drug is unionized, were used to derive a batch specific drug product particle size distribution (P-PSD). The purpose of this P-PSD is to serve as an input in physiological based pharmacokinetic (PBPK) models to calculate in vivo dissolution in various administration conditions. The P-PSD was used to predict dissolution in all other conditions tested, introducing a different Unstirred Water Layer (UWL) thickness for free- and micelle-bound drug and the calculation of surface solubility using a theoretical model. With the proposed P-PSD approach and proposed model inputs, percent dissolved at all time points and for all conditions and batches were adequately anticipated with an 11% overprediction. In contrast, the use of drug substance laser diffraction particle size data with equivalent inputs to the models led to an underprediction of observed percent dissolved by 31% overall. Finally, the use of bulk solubility instead of surface solubility led to an overall 48% overprediction of the dissolution data. Batch specific P-PSD were used to predict in vivo dissolution of acalabrutinib drug products with PBPK models. The current limitations of PBPK models for integration of in vitro dissolution are also discussed and improvements are suggested to improve future predictions.

Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems.

OBJECTIVES: The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly-soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly-soluble species, will also be discussed. KEY FINDINGS: The biphasic dissolution model utilizes media comprising immiscible aqueous and organic layers whereby the drug, following initial aqueous dissolution, partitions into the organic layer. This step, which acts to remove all dissolved species from the aqueous layer, enables further aqueous dissolution to occur and hence the dissolution-partition cycle continues. Crucially, the aqueous layer does not saturate allowing sink conditions to be maintained and hence the experiment will, in theory, yield complete dissolution. SUMMARY: This review highlights important concepts regarding solubility/sink limitation and intends to provoke debate among analytical and formulation scientists as to the potential advantages, long-term development and widespread implementation of a biphasic dissolution system in drug development.

A case study exploring the impact of an oxygen barrier coating on formulation stability, in-vitro dissolution and bioperformance.

OBJECTIVES: The impact of a carmellose sodium (sodium carboxymethycellulose)-based coat (Opaglos 2) on the stability of an oxygen-sensitive compound A and in-vitro dissolution and bioperformance of compound B has been investigated. METHODS: Tablets containing compounds A and B were coated with various weight gains of Opaglos 2 and a comparative elegance coating (poly(vinyl alcohol)-based Opadry II). Film-coated tablets were assessed for oxidative degradation under accelerated stability conditions (30°C/65% RH and 40°C/75% RH). KEY FINDINGS: An apparent rank order of restriction of oxygen (O(2) ) permeability afforded by the coatings was observed, with only higher Opaglos 2 coating weight gains (6 and 8% w/w) providing adequate oxidative degradation stability for up to 52 weeks. Improved stability at the higher coating weight gains was attributed to incomplete polymeric film formation at lower coating weight gains. The 6% and 8% w/w Opaglos 2 formulations showed dissolution retardation compared with elegance-coated formulations in USP dissolution apparatus II, predicting significant impact on formulation bioperformance. However, pharmacokinetic studies in Beagle dogs showed similar bioperformance for all formulations. CONCLUSIONS: The Opaglos 2 coating system evaluated in these studies afforded adequate protection from oxidative degradation with no negative impact on bioperformance as compared to elegance coating. However, further studies are needed using several compounds to assess the broader applicability of these coatings.

Reassessment of the tri-modal mortality distribution in the presence of a regional trauma system.

BACKGROUND: The temporal distribution of trauma-related deaths has been described as tri-modal with immediate, early, and late peaks. With the development of trauma centers and systems, it has been suggested that this distribution might be altered. METHODS: Information regarding all trauma-related deaths occurring from 1990 through 2003 in Jefferson County, AL, was obtained and the elapsed time from injury to death was calculated and categorized as <1 hour, 1 to 6 hours, 7 to 24 hours, 1 to 3 days, 4 to 7 days, and >1 week. The distribution of the time from injury to death was compared before and after the implementation (November 1, 1996) of a regional trauma system. RESULTS: Of the 5,240 deaths included in the analysis, 2,830 occurred between January 1, 1990 and October 31, 1996, before trauma system implementation, and 2,410 occurred afterward (i.e. November 1, 1996 to December 31, 2003). The temporal distribution of trauma death was significantly different (p < 0.0001) after trauma system development with a higher percentage of immediate deaths (56.3% compared with 51.4%) and a lower percentage that occurred 1 week after injury (4.8% compared with 8.1%). CONCLUSION: The development of a regional trauma system had a significant impact on the temporal distribution of trauma deaths. An increase in the proportion of immediate deaths and a decrease in the proportion of deaths that occurred >1 week after injury was observed, suggesting a shift toward a bimodal distribution.