Claudia Suenderhauf
Clinical Pharmacology & Toxicology, University Hospital Basel, Switzerland (2) Clinical Pharmacology & Toxicology, University Hospital Berne, Switzerland
Objectives:
Cytochrome P450 (CYP) enzymes are the main metabolic pathway of numerous endogenous and xenobiotic compounds. Hence, estimates of CYP activity is relevant for clinical decision making in drug therapy as well as in drug development. Drug interactions and disease states, such as inflammation or chronic liver disease, potentially alter CYP function substantially, regardless of the underlying genotype. Altered CYP function may result in changed systemic drug exposure, which in its extremes causes either increased pharmacodynamic effects, even toxicity or therapeutic failure. Hence, attempts were made assessing CPY phenotype for estimating metabolic capacity in humans in vivo. The application of CYP isoform specific probe drugs has been shown to be a safe and reliable phenotyping test: By calculating the ratio (i.e. the metabolic ratio, MR) between concentrations of parent drug and metabolite the capacity of CYP under investigation can be assessed [1][2]. As we have shown, quantitative ranking of metabolism status can be done by putting MRs in relation to ratios obtained in induced and inhibited states [2]
We selected and tested 6 CYP isoform-selective probe drugs in a clinical trial, combined in a single capsule, to reduce drug amount to low- or even micro-doses and to allow a convenient administration [3]. The aim of the present study was to select CYP isoform-selective probe drugs, combined in a single capsule and obtain PK profiles in healthy volunteers, check for tolerability, and calculate MRs. In addition, we aimed to determine a reduced optimal sampling regimen for the newly defined probe drug cocktail.
Methods:
We performed an open-label randomized 2-period crossover PK study in 12 healthy volunteers using the Basel phenotyping cocktail capsule. Non-compartmental analysis was performed for each compound using R to obtain basic PK parameters and calculate MR for each sampling time point and AUC0-12h. As a preliminary analysis, we fitted a linear model to determine sampling time points which correlate best with MRs calculated of AUC0-12.
Results:
Six substances, namely caffeine, efavirenz, flurbiprofen, metoprolol, midazolam and omeprazole were combined in a capsule formulation and administered to 12 healthy volunteers. PK profiles from parent compound and metabolite were obtained and a non-compartmental analysis was performed. MRs of single TP measurements as well as MRs of AUC0-12h were calculated. We found for caffeine (CYP1A2) and flurbiprofen (CYP2C9) one subject with rapid metabolizing phenotype, while for metoprolol (CYP2D6) there was one poor metabolizer phenotype. However, Hartigans’ Dip Test for Unimodality showed a unimodal distribution of AUC MR for all compounds in our dataset [4]. We hence concluded that we had no significant subgroups of rapid or poor metabolizers for any CYP among our sample, except these 3 individuals.
Because of large differences in PK profiles, sampling timepoints could not be collapsed to a single measurement. MRs at 2h correlated best with midazolam (CYP3A4, adj.R2: 0.89, p < 0.001) and caffeine (CYP1A2, adj.R2: 0.94, p < 0.001 ) AUC ratios, while for efavirenz (CYP2B6, adj.R2: 0.85, p < 0.001 ), flurbiprofen (CYP2C9, adj.R2: 0.99, p < 0.001), and omeprazole (CYP2C19, adj.R2: 0.85, p < 0.001 ) best fits were achieved at 6h. Metoprolol showed excellent fits at both of these timepoints (adj.R2: 0.99, p<0.001).
Conclusions: The phenotyping approach was shown to be well tolerated by all subjects and easy to perform. The information of such experiments is valuable to individualize and inform physiological and semiphysiological Models. Further studies are currently ongoing in our group to characterize patients at different stages of liver cirrhosis by means of the Basel Phenotyping capsule. In a next step, we plan to adapt a Population Optimum Design of Experiments (PODE) approach to predict MRAUC from a minimum of PK samples.
References:
[1] Donzelli, M., et al., The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots. Clin Pharmacokinet, 2014. 53(3): p. 271-82.
[2] Derungs, A., et al., Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study. Clin Pharmacokinet, 2016. 55(1): p. 79-91.
[3] Camblin, M., et al., CombiCap, a Novel Drug Formulation for the Basel Phenotyping Cocktail. Int J Pharm, 2016.[4] Hartigan J.A., et al., The Dip Test of Unimodality. Ann. Statist, 1985. 13(1) p. 70-84.
Reference: PAGE 27 (2018) Abstr 8523 [www.page-meeting.org/?abstract=8523]
Poster: Methodology - Other topics