IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 4: Prediction accuracy and software comparisons with improved data and modelling strategies.

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlus™ (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project. Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters. On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.

Pharmacokinetics of Ambroxol Sustained Release (Mucosolvan® Retard) Compared with Other Formulations in Healthy Volunteers.

INTRODUCTION: Ambroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period. METHODS: An open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18-45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1-5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUCSS 0-24) and maximum plasma level (Cmax SS). RESULTS: Twenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUCSS 0-24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar Cmax SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower Cmax SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to Cmax SS (tmax SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h). CONCLUSIONS: ER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions. CLINICALTRIALS. GOV IDENTIFIER: NCT02036775.

Ambroxol is used to relieve the symptoms of respiratory conditions in which abnormal mucus secretion is a problem, including the common cold, acute and chronic bronchitis, and chronic obstructive pulmonary disease. Different formulations of ambroxol are available, including tablets and effervescent tablets that release the drug as soon as they are digested, but need to be taken twice a day, or extended release (retard) capsules that release the drug slowly over 24 h and can be taken once a day. This randomized, three-period, six-sequence crossover study in 24 healthy volunteers compared the pharmacokinetics of three formulations of ambroxol: tablets, effervescent tablets, and retard capsules. The amount of drug in the bloodstream over 24 h was similar with all three formulations, but (as expected) the time to reach peak plasma concentration was longer with the retard capsules than both forms of tablet. These results show that people who take ambroxol for respiratory conditions will receive the same amount of ambroxol whether they take retard capsules, standard tablets, or effervescent tablets.

IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.

Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.

Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug.

The in vitro metabolism of dronedarone and its major metabolites has been studied in human liver microsomes and cryopreserved hepatocytes in primary culture through the use of specific or total cytochrome P450 (CYP) and monoamine oxidase (MAO) inhibitors. The identification of the main metabolites and enzymes participating in their metabolism was also elucidated by using rhCYP, rhMAO, flavin monooxygenases (rhFMO) and UDP-glucuronosyltransferases (rhUGT) and liquid chromatography/tandem mass spectrometry (LC/MS-MS) analysis. Dronedarone was extensively metabolized in human hepatocytes with a metabolic clearance being almost completely inhibited (98 ± 2%) by 1-aminobenzotriazole. Ketoconazole also inhibited dronedarone metabolism by 89 ± 7%, demonstrating the crucial role of CYP3A in its metabolism. CYP3A isoforms mostly contributed to N-debutylation while hydroxylation on the butyl-benzofuran moiety was catalyzed by CYP2D6. However, hydroxylation on the dibutylamine moiety did not appear to be CYP-dependent. N-debutyl-dronedarone was less rapidly metabolized than dronedarone, the major metabolic pathway being catalyzed by MAO-A to form propanoic acid-dronedarone and phenol-dronedarone. Propanoic acid-dronedarone was metabolized at a similar rate to that of N-debutyl-dronedarone and was predominantly hydroxylated by CYP2C8 and CYP1A1. Phenol-dronedarone was extensively glucuronidated while C-dealkyl-dronedarone was metabolized at a slow rate. The evaluation of the systemic clearance of each metabolic process together with the identification of both the major metabolites and predominant enzyme systems and isoforms involved in the formation and subsequent metabolism of these metabolites has enhanced the overall understanding of metabolism of dronedarone in humans.

Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers.

OBJECTIVE: Patients undergoing major orthopaedic surgery who are being treated with fondaparinux sodium for prevention of venous thromboembolism may be receiving treatment for coronary artery disease or chronic inflammatory disease of the joints or arthritis. Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers. DESIGN: In the first study a single dose of aspirin 975mg was assessed initially, followed by single doses of aspirin or placebo on the fourth day of an 8-day regimen of subcutaneous fondaparinux sodium (10mg once daily). The second study was a three-way crossover, double-blind, randomised study which investigated fondaparinux sodium 10mg + placebo, fondaparinux sodium 10mg + piroxicam 20mg, or placebo + piroxicam 20mg. METHODS: Both studies obtained plasma concentration-time profiles of fondaparinux sodium administered alone and with aspirin or piroxicam. Noncompartmental parameters - peak concentration, trough concentration, time to reach peak concentration, and area under the concentration-time curve - were obtained. Both studies measured the pharmacodynamic parameters bleeding time and activated partial thromboplastin time (aPTT). Safety was monitored. RESULTS AND CONCLUSIONS: Neither aspirin nor piroxicam influenced the pharmacokinetics of fondaparinux sodium at steady state. Two hours after administration, prolongation of bleeding time with aspirin alone or with aspirin plus fondaparinux sodium was significantly greater than with fondaparinux sodium alone (p = 0.003 and p = 0.004, respectively). No significant differences were observed between aspirin alone or aspirin + fondaparinux sodium in effect on bleeding time. A small decrease in collagen-induced platelet aggregation was observed after administration of piroxicam alone or piroxicam + fondaparinux sodium. A small effect on aPTT was observed; it was similar for fondaparinux sodium whether administered alone or in combination with either aspirin or piroxicam. No serious adverse events were reported.

Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers.

OBJECTIVE: Fondaparinux sodium is the first of a new class of antithrombotic agents: the selective factor Xa inhibitors. Coadministration with digoxin may occur in clinical practice and both drugs are excreted almost completely by the renal route. In this study we assessed the possible pharmacokinetic and pharmacodynamic interaction of fondaparinux sodium with digoxin at steady state in healthy male volunteers. DESIGN: In a phase I randomised, crossover study, volunteers (n = 24) were treated in two periods. The first period was once-daily administration of fondaparinux sodium 10mg subcutaneously alone for 7 days; the second period was 7 days of digoxin 0.25mg orally alone followed by 7 days of coadministration with fondaparinux sodium 10mg. Each period was separated by a washout of 12 days. METHODS: Urinary volumes, plasma concentration-time profiles and noncompartmental pharmacokinetic parameters of fondaparinux sodium and digoxin were obtained at steady state, following administration alone or together for each period. A bioequivalence approach was taken to assess interaction. Pharmacodynamic parameters were supine blood pressure and heart rate and the ECG parameters PR interval, QRS interval, QT interval and QT(c). The safety of the treatments was monitored. RESULTS AND CONCLUSIONS: The pharmacokinetic profiles of both digoxin and fondaparinux sodium were unaffected by coadministration. Bioequivalence was concluded, based on the 90% confidence intervals of the ratio of adjusted geometric means calculated for the 2-by-2 comparison of peak concentration, area under the concentration-time curve and cumulative urinary excretion, which lay within the 0.80 to 1.25 reference interval. There were no clinically significant fluctuations in vital signs and ECG parameters. The coadministration of digoxin with fondaparinux sodium was well tolerated and no significant changes were observed in vital signs.