Objective Ambulatory saliva collections for subsequent analysis of free cortisol levels are now frequently applied to measure adrenocortical activity in healthy subjects and patient populations. Despite the prime importance of accurate timing of saliva collection outside the laboratory, no data are available on the compliance of study participants following a given sampling protocol. This study investigated how accurately subjects adhered to the instructions to collect six saliva samples throughout 1 day. Methods Subjects were instructed to collect six saliva samples throughout 1 day (directly after awakening, 30 minutes after awakening, 11 AM, 3 PM, 8 PM, 10 PM). Objective compliance was measured using an electronic monitoring device given to the subjects either with ("informed" N = 23) or without ("noninformed" N = 24) their knowledge of the nature of the device. Data on subjective compliance were obtained by self-report. Results Thirty-one subjects (74%) were found to comply with the sampling instructions, and 11 (26%) failed at least once to obtain the saliva sample at the correct time of day. Nine of the 11 noncompliant subjects (82%) had two or more noncompliant samples. Fifty-five percent (6 of 11) of the noncompliant subjects took sample 2 outside the sampling window. The circadian cortisol profile differed significantly between compliant and noncompliant subjects (F = 7.98, p =.007). The most important effect of compliance was seen in the rise of cortisol at awakening. Compliant subjects showed a robust increase, whereas noncompliant individuals had only minimal changes from baseline at 30 minutes after awakening (t = 2.89, p =.007). Thus the steepness of the circadian cortisol decline was greater for compliant subjects (t = 2.10, p =.043). Furthermore, the informed group adhered more closely to the sampling protocol than the noninformed subjects (p =.001). Self-reported compliance also differed significantly between study groups (p =.03). In the noninformed group, self-reported sampling accuracy was significantly higher than objectively measured compliance (p =.03); the two measures were similar in the informed group (p = NS). Conclusions A significant number of subjects did not obtain saliva samples reliably in an ambulatory setting. This can partially invalidate the cortisol results and mask potential differences between subject groups of interest. We therefore recommend the use of electronic monitoring devices or other suitable methods and that study participants be informed about the device when ambulatory saliva collection is performed.

Compliance with saliva sampling protocols: electronic monitoring reveals invalid cortisol daytime profiles in noncompliant subjects.

Adherence in AIDS clinical trials: a framework for clinical research and clinical care.

We attempted to assess compliance using both a pharmacologic indicator (low-dose phenobarbital) and a return tablet count in 225 patients who were taking part in three separate studies. There were 216 patients (96%) who kept a follow-up appointment after 28 days; 161 patients appeared to have good compliance (90% to 109%) by return tablet count. Of these 161 patients, 51 (32%) had plasma phenobarbital concentrations (corrected for dose and weight) that were less than 90% of the lowest value previously found in normal volunteers, which suggested poorer compliance. When compared with the age-related volunteer values, 77 (48%) had values that were less than 90% of the lowest volunteer value. There were 6 of 10 patients with apparently excessive (greater than or equal to 110%) compliance by return tablet count and 4 of 12 who failed to return their container who also had phenobarbital concentrations that were less than 90% of the lowest volunteer value. We concluded that return tablet count grossly overestimates compliance.

Time to stop counting the tablets

Until 1986 to 1987, the estimation of patient compliance with prescribed drug regimens in ambulatory care relied on methods that were biased either by their subjectivity or by the improvement in compliance that commonly occurs during the day or two prior to a scheduled examination, so called ‘white-coat compliance’.

Role of patient compliance in clinical pharmacokinetics. A review of recent research.

By use of an interview, return tablet count, and a pharmacologic indicator (low-dose phenobarbital), we compared compliance with tablets prescribed to be taken once, twice, or three times daily. One hundred seventy-nine patients with type II diabetes were randomly allocated to take one 2 mg phenobarbital tablet once, twice, or three times daily for 28 days. Phenobarbital level/dose ratios indicated that compliance was similar with once- and twice-daily regimens, and both were better than thrice-daily dosing. Mean return tablet counts suggested that compliance was best with the once-daily regimen; both twice- and thrice-daily regimens were similarly inferior. This difference between the techniques may be explained by the inadequacies of the residual tablet count, which identified only 13% of cases identified by phenobarbital. We conclude that compliance with the once-daily regimen was best, but that compliance with a twice-daily regimen was very similar, and both were superior to dosing three times a day.

Use of a pharmacologic indicator to compare compliance with tablets prescribed to be taken once, twice, or three times daily.

Low-dose phenobarbitone asanindicator ofcompliance with drugtherapy

1 To assess the potential value of low-dose phenobarbitone (PB) as a marker of compliance we studied the relationship between plasma level of PB and dose (2-16 mg daily) following 3 or 4 weeks treatment in healthy volunteers (n = 26) and in-patient volunteers (n = 7). 2 Also, to simulate poor compliance, PB levels were measured in some volunteers following alternate-day (n = 6) or short-term (n = 5) treatment with similar doses. These levels, expressed as the level: dose ratios (LDRs), did not overlap with those obtained following 3 or 4 weeks of daily PB intake. 3 To evaluate the efficacy of this marker in patients taking other drugs we gave a group of out-patients (n = 24) compound tablets containing B vitamins and a small dose (16 mg) of PB; their compliance over 2-5 weeks was assessed both by measuring plasma levels of PB and residual tablet counting. 4 In the latter study, as well as providing absolute evidence of good compliance by many patients, the plasma levels of PB proved particularly valuable when non-compliant individuals 'forgot' to bring their residual tablets. 5 We suggest that phenobarbitone, in doses low enough to be non-sedative and non-enzyme inducing, is potentially useful as a pharmacological indicator of compliance with drug therapy.

Low‐dose phenobarbitone as an indicator of compliance with drug therapy.

The effects of low-dose phenobarbitone on three indices of hepatic enzyme induction were studied. Eight healthy volunteers took phenobarbitone 7.5 mg daily for 4 weeks followed by 15 mg daily for 4 weeks; five subjects took 30 mg daily for a further 2 weeks. Phenobarbitone 15 mg daily produced a significant rise in antipyrine clearance (P less than 0.05). Phenobarbitone 30 mg daily produced a further rise, but probably because of the reduced numbers of subjects, this did not achieve significance (P = 0.06). Urinary 6-beta-hydroxycortisol and D-glucaric acid levels did not change significantly and remained within the range seen in subjects not taking enzyme-inducing drugs. We conclude that phenobarbitone 7.5 mg daily produces little (if any) enzyme induction whereas 15 mg, or more, may have the potential to produce drug interactions through enzyme induction.

The effect of low-dose phenobarbitone on three indices of hepatic microsomal enzyme induction

http://www.portlandpresspublishing.com/content/ppclinsci/67/s9/28P.2.full.pdf

A. Mehta

Papers

Low-dose phenobarbitone asanindicator ofcompliance with drugtherapy

Low‐dose phenobarbitone as an indicator of compliance with drug therapy.

The effect of low-dose phenobarbitone on three indices of hepatic microsomal enzyme induction

Use of Low-Dose Phenobarbitone to Assess Patient Compliance