A Pharmacokinetic Study Examining Acetazolamide as a Novel Adherence Marker for Clinical Trials

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 sub-therapeutic (microdose) of acetazolamide as a medication ingestion marker, because acetazolamide is rapidly absorbed and excreted without metabolism in urine and can be non-invasively sampled. Methods In a double-blind, placebo-controlled, residential study, ten volunteers received 15 mg oral acetazolamide for four 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±18.5h, mean±SD, n=6), resulted in the acetazolamide microdose exhibiting a substantially longer plasma half-life (24.5±5.6 h, n=10) than previously reported for therapeutic doses (3–6 h). Following 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 inter-subject variability and a half-life of 16.1±3.8h (n=10). For each of four consecutive mornings after dosing cessation, the rates of urinary acetazolamide elimination remained quantifiable. There was no overall effect of acetazolamide on the pharmacodynamics, Cmax, Tmax 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 two days when oxycodone was given alone, but there were no observed effects of acetazolamide on oxycodone pharmacodynamic responses. Conclusions Co-formulation of a once-daily trial medication with an acetazolamide microdose may allow estimation of the last time of medication consumption for up to 96h post-dose. Inclusion of acetazolamide may, therefore, provide an inexpensive new method to improve estimates of medication adherence in clinical trials.

Subtherapeutic Acetazolamide Doses as a Noninvasive Method for Assessing Medication Adherence

“…Previously published UKY data demonstrated that ACZ and oxycodone pharmacokinetics are mutually noninteractive when concomitantly administered. 4 Clearly, such a lack of pharmacokinetic interaction between studied medication and adherence marker is essential for any viable adherence marker excipient. The high degree of reproducibility in the ACZ decay curves in all three of the trials conducted to date ( Table 1 and Figure 3b) demonstrates that ACZ output is unaffected by concomitant treatment with cocaine, quinine, doxazosin, modafinil, or oxycodone (please see Figure S1 to compare drug administration protocols in the different cohorts).…”

“…3 In 2016, we reported on subtherapeutic (15 mg) acetazolamide (ACZ) doses as a promising noninvasive adherence marker. 4 We used ACZ because it is completely excreted in urine, 5 has been US Food and Drug Administration (FDA)-approved since 1953, and is not physiologically present. It is typically used in doses of 250 and 500 mg twice daily, although in elderly populations it is used to treat congestive heart failure at doses of 125-250 mg/day.…”

“…We previously confirmed that the lactose excipient does not affect ACZ's dissolution profile. 4 Urine sample preparation and analytical methods Deuterated ACZ internal standard (250 µL) was added to 50 µL of urine, which were vortex-mixed, separated by centrifugation, and transferred to autosampler vials. Fifteen to 30 µL of each sample was injected onto a liquid chromatography-tandem accurate mass spectrometry and separated over a 5 µm, 4.6 × 100 mm C18 column at room temperature, using an isocratic mobile phase, consisting of 15 MeOH: 85 H 2 O: 0.05 HCOOH, 2.5 mM NH 4 HCOOat a flow rate of 1 mL/min.…”

“…We conclude that inclusion of 15 mg ACZ as a dosage form adherence marker excipient, provides a reliable and sensitive mechanism to confirm medication consumption and detect nonadherence during clinical efficacy trials. 1 Division of Therapies and Medical Consequences, National Institute on Drug Abuse, Rockville, Maryland, USA; 2 Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, USA; 3 McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA; 4 Department of Psychiatry, Baylor College of Medicine, Houston, Texas, USA; 5 Research Service Line, Department of Veterans Affairs, Michael E. DeBakey VA Medical Center, Houston, Texas, USA; 6 Travis County Medical Examiner's Office, Austin, Texas, USA; 7 Institute on Emerging Health Professions, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. *Correspondence: Aidan J.…”

Use of a Single CAR T Cell and Several Bispecific Adapters Facilitates Eradication of Multiple Antigenically Different Solid Tumors

“…A schedule of escalating CAM doses (i.e., 5 nmol/kg on days 1 and 2, 50 nmol/kg on days 4 and 6, 100 nmol/kg on days 8 and 10, and 500 nmol/kg from day 12 onward; Supplementary Table S1) was invariably used, because it was found from a systematic analysis of various dosing concentrations and frequencies to yield complete tumor elimination with no apparent toxicity. Analysis of the pharmacokinetic of FITC-folate in both animals and humans has been reported elsewhere (20), and an evaluation of the pharmacokinetics of the PSMA, CA IX, and NK1R ligands has also been reported (21)(22)(23).…”