Physiological Study of the Human CYP3A Activity (PiSA) (PiSA)

Investigator-initiated physiological study to characterize the function of a major drug metabolizing enzyme using a microdosed phenotyping probe to avoid unwanted, concentration-dependent effects.

Study Overview

• Status: Completed
• Conditions: Cytochrome P450 CYP3A Enzyme Deficiency
• Intervention / Treatment: Drug: AB (Midazolam OD formulation/Dormicum); Drug: BA (Dormicum/Midazolam OD formulation)

Detailed Description

Disposition of a drug depends on absorption, distribution, metabolism, and elimination (ADME). Quantifying the ADME capacity of a patient may help to individualize target exposure by choosing the corresponding dose required for this individual. The large group of drugs eliminated by members of the CYP3A isozyme subfamily accounts for about 50% of all marketed drugs. Co-medication can modulate CYP3A activity 400-fold either by inducing isozyme expression or inhibiting expressed enzyme. Therefore, due to the variability of CYP3A activity, dose requirements of CYP3A substrates vary considerably between individual patients and may even rapidly vary within a patient. There is clinical interest in using CYP3A activity as a biomarker to predict optimal CYP3A drug dosing, improve therapeutic efficacy, and minimize adverse drug effects.

Determination of CYP3A activity is usually done with oral midazolam doses of 2-7.5 mg (phenotyping). Because therapeutic doses have pharmacological effects and can cause sedation, especially if CYP3A is inhibited, a microdosing approach for CYP phenotyping was developed to avoid any pharmacological activity. Oral midazolam pharmacokinetics are linear over a 30,000-fold range and 300 ng doses can reliably predict drug interactions with strong CYP3A inhibitors like ketoconazole.

The primary objective of this trial is to determine CYP3A activity using microdosed midazolam delivered from an oral disintegrating formulation in comparison to an oral midazolam solution. The oral disintegrating formulation is an innovative application form that would facilitate administration of the phenotyping probe in special patient populations.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• Switzerland
  • Basel Stadt
    • Basel, Basel Stadt, Switzerland, 4031
      • University Hospital Basel,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male or female subjects, age of 18 to 50 years, body mass index (BMI) of 18.0 to 29.9 kg/m2

Exclusion Criteria:

• Any intake of a substance known to induce or inhibit drug metabolising enzymes or transport system enzymes within a period of less than 10 times the respective elimination half-life or 3 weeks (whatever is longer).
• Any participation in a clinical trial within the last four weeks before inclusion.
• History or clinical evidence of any disease or medical condition, which may interfere with the pharmacokinetics of midazolam or which may increase the risk for toxicity or adverse events.
• Allergies (except for mild forms of hay fever) or history of hypersensitivity reactions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AB (Midazolam OD/Dormicum); Subjects with sequence AB will first receive the Intervention OD formulation (Period A, 30 µg Midazolam) and at the second visit the oral solution (Period B, 30 µg Dormicum ).	Drug: AB (Midazolam OD formulation/Dormicum); Oral disintegrating formulation (Midazolam OD Formulation). The Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd; Other Names: oral disintegrating (OD) formulation containing midazolam
Experimental: BA (Dormicum/midazolam OD); Subjects with sequence BA will first receive the Intervention oral solution (Period B, 30 µg Dormicum) and at the second visit the OD disintegrating formulation (Period A, 30 µg Midazolam).	Drug: BA (Dormicum/Midazolam OD formulation); Oral disintegrating film (Midazolam OD Formulation). The Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd; Other Names: oral disintegrating (OD) formulation containing midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC0-12 of midazolam in plasma	Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd. and is provided free of charge in support of the present study.	0,1,2,3,4,5,6,7,8,9,10,11,12 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of midazolam in plasma	Midazolam OD Formulation was developed by Kyukyu Pharmaceutical Co., Ltd. and is provided free of charge in support of the present study.	0,1,2,3,4,5,6,7,8,9,10,11,12 hours

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Stephan Krähenbühl, University Hospital, Basel, Switzerland

Publications and helpful links

General Publications

• Kiene K, Hayasi N, Burhenne J, Uchitomi R, Sunderhauf C, Schmid Y, Haschke M, Haefeli WE, Krahenbuhl S, Mikus G, Inada H, Huwyler J. Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film. Eur J Pharm Sci. 2019 Jul 1;135:77-82. doi: 10.1016/j.ejps.2019.05.010. Epub 2019 May 16.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2017
• Primary Completion (Actual): September 25, 2017
• Study Completion (Actual): September 25, 2017

Study Registration Dates

• First Submitted: June 22, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: April 17, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: 2017-00545; me16Haschke (Other Identifier: CTU Basel)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No