The prediction of steady‐state plasma phenobarbitone concentrations (following low‐dose phenobarbitone) to refine its use as an indicator of compliance.

Abstract

1. A model for predicting the steady‐state plasma concentration of phenobarbitone following low‐dose phenobarbitone used as an indicator of compliance was derived using data for 10 healthy volunteers. 2. Each volunteer was given a single 30 mg oral dose of phenobarbitone and the pharmacokinetics were described. Subsequently, volunteers were given phenobarbitone 2 mg daily for 28 days and a further pharmacokinetic profile determined during and after this period. 3. An initial predicted estimate of steady‐state plasma drug concentration was made using each volunteer's demographic details. This estimate was revised by Bayesian analysis using single timed samples (24, 48, 72 or 96 h) following the single dose. 4. The model was tested on a further 10 healthy volunteers given a single 8 mg dose and who were subsequently given 2 mg daily for 28 days. 5. The revised estimate of peak steady‐ state plasma phenobarbitone concentration utilising the 96 h post‐ single dose concentration (356 ng ml‐1) was least biased (mean prediction error +/‐ 95% CI = 10.6 +/‐ 19.8 ng ml‐1) and most precise (root mean square error +/‐ 95% CI = 28.3 +/‐ 19.0 ng ml‐1). In all cases the peak or trough steady‐state drug concentration was within 13% of the predicted value. 6. The model reflected compliance accurately in a further eight volunteers with simulated partial (two‐thirds) compliance. 7. The use of a predictive model using Bayesian analysis to estimate expected steady‐state plasma phenobarbitone concentrations could increase further the usefulness of low‐dose phenobarbitone as an indicator of compliance.

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

“…Little change is noted through childhood (37 h) but the half-life increases as patients reach adulthood (73-139 h; Garrettson & Dayton, 1970;Wilenski et al, 1982). Phenobarbital clearance is higher in children (5.3-14.1 mL/kg/hr) compared to adults (2.1-4.9 mL/kg/h; Nelson et al, 1982;Wilensky et al, 1982;Browne et al, 1985;Pullar et al, 1991).…”

Limits of Confidence in Tracer Compounds as a Means of Measuring Patient Compliance with Medication

“…Pullar and colleagues at Leeds, in a 1991 experiment involving 8 subjects, simulated two-thirds compliance (18 regularly spaced doses) with phenobarbital over 28 days. 24 The authors compared peak and trough levels on the final day of dosing with predictions drawn from measured kinetics in a different population. Seven of these subjects had previously participated in a study of full compliance dosing, and their peak and trough levels after full compliance were therefore known.…”

“…For all tracers, we chose kinetic parameters and doses similar to those in the phenobarbital literature. 24 We therefore postulated a loading dose of 30 mg for each compound, given on day 0, and a volume of distribution of 35 liters. Based on assigned half-life and volume of distribution, washout serum levels were calculated for each compound 1 day after the loading dose and on days equal to 0.5, 1, 1.5, and 2 times the assigned half-life.…”

Accounting for Noncompliance in the Design of Clinical Trials

“…Certain chemical markers incorporated into the medication may be more conveniently monitored than levels of the drug itself or its metabolites. For example, riboflavin has been used as a marker to assess compliance with antihypertensive agents (18) (see, for example, [19,20] for a discussion of other markers).…”