Clinical pharmacology in drug development
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Clin Pharmacol Drug Dev · Nov 2019
A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.
GW Pharmaceuticals' formulation of highly purified cannabidiol oral solution is approved in the United States for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥2 years, for which clobazam, stiripentol, and valproate are commonly used antiepileptic drugs. This open-label, fixed-sequence, drug-drug interaction, healthy volunteer trial investigated the impact of cannabidiol on steady-state pharmacokinetics of clobazam (and N-desmethylclobazam), stiripentol, and valproate; the reciprocal effect of clobazam, stiripentol, and valproate on cannabidiol and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]); and cannabidiol safety and tolerability when coadministered with each antiepileptic drug. Concomitant cannabidiol had little effect on clobazam exposure (maximum concentration [Cmax ] and area under the concentration-time curve [AUC], 1.2-fold), N-desmethylclobazam exposure increased (Cmax and AUC, 3.4-fold), stiripentol exposure increased slightly (Cmax , 1.3-fold; AUC, 1.6-fold), while no clinically relevant effect on valproate exposure was observed. ⋯ There was no effect of valproate on cannabidiol or its metabolites. Cannabidiol was moderately well tolerated, with similar incidences of adverse events reported when coadministered with clobazam, stiripentol, or valproate. There were no deaths, serious adverse events, pregnancies, or other clinically significant safety findings.
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Clin Pharmacol Drug Dev · Aug 2019
Randomized Controlled TrialThe Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. ⋯ Treatment-emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high-fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.
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Clin Pharmacol Drug Dev · May 2019
Clinical TrialA Cocktail Interaction Study Evaluating the Drug-Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels.
ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). ⋯ Overall, ASP8477 was a weak inhibitor for CYP3A4 and CYP2C9, a moderate to strong inhibitor for CYP2C19, and a weak to strong inhibitor for CYP2D6, with doses from 20 to 100 mg. This study confirmed that the Inje cocktail approach was able to detect relevant drug-drug interactions impacting further development of ASP8477 and future therapeutic use. With the approach used here, the inhibiting effect of a perpetrator drug on different CYP enzymes can be evaluated, and at different doses, thereby supporting dose recommendations for potential interactions.
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Clin Pharmacol Drug Dev · Apr 2019
Randomized Controlled TrialEvaluation of Food and Spherical Carbon Adsorbent Effects on the Pharmacokinetics of Roxadustat in Healthy Nonelderly Adult Male Japanese Subjects.
Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in chronic kidney disease. Spherical carbon adsorbent (SCA) is used in patients with chronic kidney disease and has been shown to impact absorption of certain concomitant drugs. Two phase 1, open-label, randomized, crossover studies were conducted in healthy adult Japanese males to investigate the effect of food and SCA on the pharmacokinetics of a single oral dose of roxadustat. ⋯ In the SCA/roxadustat drug-drug interaction study, all geometric mean ratios and 90% confidence intervals (roxadustat + SCA/roxadustat) were within the no-effect boundaries of 80% and 125%. Roxadustat was generally well tolerated. The effect of food on the pharmacokinetics of roxadustat and the drug-drug interaction between roxadustat and SCA do not appear to be clinically relevant and support the safe use of roxadustat under these conditions.
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Clin Pharmacol Drug Dev · Jan 2019
Randomized Controlled TrialPharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets.
Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. ⋯ For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent.