Abstract
Rationale Accurate assessment of medication adherence is critical for determination of medication efficacy in clinical trials, but most current methods have significant limitations. This study tests a subtherapeutic (microdose) of acetazolamide as a medication ingestion marker because acetazolamide is rapidly absorbed and excreted without metabolism in urine and can be noninvasively sampled. Methods In a double-blind, placebo-controlled, residential study, 10 volunteers received 15 mg oral acetazolamide for 4 consecutive days. Acetazolamide pharmacokinetics were assessed on day 3, and its pharmacokinetic and pharmacodynamic interactions with a model medication (30 mg oxycodone) were examined on day 4. The rate of acetazolamide elimination into urine was followed for several days after dosing cessation. Results Erythrocyte sequestration (half-life = 50.2 ± 18.5 h, mean ± SD, n = 6), resulted in the acetazolamide microdose exhibiting a substantially longer plasma half-life (24.5 ± 5.6 hours, n = 10) than previously reported for therapeutic doses (3-6 hours). After cessation of dosing, the rate of urinary elimination decreased significantly (F 3,23 = 247: P < 0.05, n = 6) in a predictable manner with low intersubject variability and a half-life of 16.1 ± 3.8 h (n = 10). For each of 4 consecutive mornings after dosing cessation, the rates of urinary acetazolamide elimination remained quantifiable. There was no overall effect of acetazolamide on the pharmacodynamics, C max, T max, or elimination half-life of the model medication tested. Acetazolamide may have modestly increased overall oxycodone exposure (20%, P < 0.05) compared with one of the 2 days when oxycodone was given alone, but there were no observed effects of acetazolamide on oxycodone pharmacodynamic responses. Conclusions Coformulation of a once-daily trial medication with an acetazolamide microdose may allow estimation of the last time of medication consumption for up to 96 hours postdose. Inclusion of acetazolamide may therefore provide an inexpensive new method to improve estimates of medication adherence in clinical trials.
| Original language | English |
|---|---|
| Pages (from-to) | 324-332 |
| Number of pages | 9 |
| Journal | Journal of Clinical Psychopharmacology |
| Volume | 36 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 1 2016 |
Bibliographical note
Funding Information:The authors thank the staff at the University of Kentucky (UK) Center on Drug and Alcohol Research for research support, the UK CCTS Laboratory for assistance with specimens, the UK Investigational Pharmacy for preparing study medication, UK CCTS Inpatient Unit nursing staff for patient care, and Dr Samy-Claude Elayi (UK Department of Cardiology, Gill Heart Institute) for patient support. The authors also thank Dr Nora Chiang at the National Institute onDrug Abuse for her pharmacokinetic expertise and support. Neither Dr Hampson nor Dr Krieter had Programmatic responsibility for R01DA016718-08S1 (S.L.W.), the National Institute on Drug Abuse grant that supported the conduct of this work. The authors also acknowledge nursing and inpatient support from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, UL1TR000117.
Publisher Copyright:
© 2016 Wolters Kluwer Health, Inc.
Keywords
- acetazolamide
- adherence marker
- erythrocyte sequestration
- ingestion marker
ASJC Scopus subject areas
- Psychiatry and Mental health
- Pharmacology (medical)
