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Adherence monitoring is a vital component of clinical efficacy trials, as the regularity of medication consumption affects both efficacy and adverse effect profiles. Pill-counts do not confirm consumption, and invasive plasma assessments can only assist post hoc assessments. We previously reported on the pharmacokinetics of a potential adherence marker to noninvasively monitor dosage consumption during a trial without breaking a blind. We reported that consumption cessation of subtherapeutic 15 mg acetazolamide (ACZ) doses showed a predictable urinary excretion decay that was quantifiable for an extended period. The current study describes the clinical implementation of 15 mg ACZ doses as an adherence marker excipient in distinct cohorts taking ACZ for different "adherence" durations. We confirm that ACZ output did not change (accumulate) during 18-20 days of adherence, and developed and assessed urinary cutoffs as nonadherence indicators. We demonstrate that whereas an absolute concentration cutoff (989 ng/mL) lacked sensitivity, a creatinine normalized equivalent (1,376 ng/mg ACZ) was highly accurate at detecting nonadherence. We also demonstrate that during nonadherent phases of three trials, creatinine-normalized urinary ACZ elimination was reproducible within and across trials with low variability. Excretion was first order, with a decay half-life averaging ~ 2.0 days. Further, excretion remained quantifiable for 14 days, providing a long period during which the date of last consumption might be determined. 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., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Objectives: Determine the diuretic effects of single intravenous doses of bumetanide in volume-overloaded critically ill infants., Methods: A prospective, open-label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug., Results: Peak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 micrograms/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of > 10 micrograms/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses., Conclusions: Maximal diuretic responses occurred at a bumetanide excretion rate of about 7 micrograms/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low-dose boluses may produce optimal diuretic responses in critically ill infants.

Objective: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants., Methods: A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques., Results: Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% +/- 15% of the administered dose., Conclusions: Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months.

We assessed the response to and handling of furosemide and bumetanide in 30 experiments with the former and 46 with the latter in normal subjects. Oral doses of furosemide (20, 40, and 80 mg) were used, and subjects received oral doses of 0.5, 1, and 2 mg bumetanide and intravenous doses of 0.5 and 1 mg bumetanide. both drugs were quickly absorbed and peak urinary amounts were reached at 75 min (median). Approximately 30% of an oral dose of each drug was excreted unchanged in the urine with no evidence of dose-dependent elimination. After intravenous injection, 36% of the bumetanide was excreted unchanged. Consequently, bumetanide has an estimated bioavailability of 80% (approximately 40% for furosemide). The relationship between the logarithm of the urinary bumetanide excretion rate and the logarithm of the sodium excretion rate was described by a sigmoid-shaped dose-response curve, with a dose inducing half-maximal response of 1 +/- 0.04 micrograms/min; it was 69.8 micrograms/min for furosemide. Overall, the distinguishing features between the two drugs are the 200% greater bioavailability and the much greater potency of bumetanide.