Romulus K. Brazzell

Pharmacokinetics of the retinoids isotretinoin and etretinate: A comparative review

The clinical pharmacokinetic profiles of two orally administered retinoids, isotretinoin and etretinate, are discussed and compared. The pharmacokinetic profile of isotretinoin is predictable and can be described using linear pharmacokinetic theory. The drug is rapidly absorbed following oral administration, is highly bound to plasma protein, and is metabolized to 4-oxo-isotretinoin. The apparent half-lives of elimination of isotretinoin and 4-oxo-isotretinoin following the oral administration of isotretinoin range from 10 to 20 hours and 24 to 29 hours, respectively. Steady-state pharmacokinetic profiles in patients are consistent with the single-dose pharmacokinetics in normal subjects. Following oral administration, etretinate undergoes significant first-pass biodegradation to its corresponding carboxylic acid; the acid appears rapidly in the circulation, often earlier than the parent drug, and its plasma concentration is usually comparable to, or greater than, that of the parent drug. The apparent elimination rates of drug and metabolite are similar (6-13 hours) following a single dose, suggesting that metabolite elimination may be formation-rate limited. During multiple dosing of etretinate, a very slow terminal elimination phase is observed which is not detected after single-dose administration. The prolonged half-life of this phase suggests accumulation in a deep tissue compartment. Differences between the two retinoids reflect their differing physicochemical properties.

Cibenzoline plasma concentration and antiarrhythmic effect

The relationship between plasma concentrations of cibenzoline and its antiarrhythmic effect was evaluated in patients receiving the drug orally as part of an ascending multiple dose efficacy and tolerance study. Twenty‐five patients participated in a 3‐day placebo period, 3 days of 32.5 mg cibenzoline every 6 hr, 3 days of 65 mg cibenzoline every 6 hr, 3 days of 81.25 mg cibenzoline every 6 hr, and 3 final placebo days. Arrhythmia frequency was monitored by 24‐hr Holter monitoring and blood samples were drawn during and after dosing. Percent reduction in baseline premature ventricular complex (PVC) frequency for the 25 subjects demonstrated considerable interpatient variability in antiarrhythmic response. Cibenzoline plasma concentrations over 300 ng/ml were associated with some decrease in PVC frequency in virtually all cases. The relationship between plasma concentration and PVC frequency was studied more rigorously in eight of the 25 patients and that for ventricular couplet (VC) frequency was studied in six. For these analyses, PVC and VC frequency data were averaged over 6‐hr intervals and plotted against trough cibenzoline concentrations. The data from each patient were fitted with a concentration‐effect function (Hill equation) by means of least squares regression. With the exception of two extreme values, the concentration corresponding to 90% reduction in PVC frequency (C90) ranged from 215 to 405 ng/ml. In five of the six patients with arrhythmia in whom VC data were also evaluated, the individual C90 for VCs were considerably less than those for PVCs. The agreement between the observed concentration‐response relationships and those predicted by curve‐fitting the data suggests that the antiarrhythmic effect of cibenzoline is proportional to its plasma concentration, and that the Hill equation provides an accurate mathematic description of the concentration‐response relationship.

Age and cibenzoline disposition

Oral cibenzoline kinetics were followed in 36 healthy subjects aged from 22 to 78 yr divided into groups of six subjects per decade between 20 and 80 yr. Each received a single, oral, 160‐mg dose of cibenzoline. Blood and urine samples were collected for 72 hr. Cibenzoline plasma and urine concentrations were measured by HPLC. Maximum plasma cibenzoline concentrations (Cmax) ranged from 283 to 1100 ng/ml and occurred 1 to 2.5 hr after dosing. Apparent oral clearance (ClT) ranged from 401 to 1677 ml/min and the t½ ranged from 5.9 to 13.4 hr. Nonrenal clearance (ClNR) ranged from 65 to 1113 ml/min, renal clearance (ClR) ranged from 165 to 645 ml/min, and 31% to 86% of the dose was recovered unchanged in urine (Xu). The volume of distribution (Vd) was large, ranging from 236 to 948 l. There was a significant relationship between age and the following kinetic parameters: Cmax, Xu, t½ (all of which increased with age), ClT, ClR, ClNR, the terminal elimination rate constant β, and Vd (which decreased with age). Mean ClT was 999 ± 371 ml/min in the 20‐ to 30‐yr age group and was 465 ± 78 ml/min in the 70‐ to 80‐yr age group. The change in ClT with age resulted from a decrease in both ClR and ClNR. Mean t½ varied from 7 hr in the youngest group to 10.5 hr in the oldest group. The age‐related changes in cibenzoline kinetics occurred over the entire age range studied and the relationship between age and these kinetic parameters appeared to be linear. Multiple regression analyses showed that ClT, ClR, and Vd were related to sex, age, and serum creatinine concentration, which suggests that these variables may be essential in the clinical individualization of cibenzoline dosing.

Single-dose pharmacokinetics and dose proportionality of oral cibenzoline

Abstract: The pharmacokinetics of cibenzoline were evaluated in four young healthy volunteers who received ascending oral doses of 65, 97.5, 130, 162.5, 195, 227.5, and 260 mg separated by one week. Cibenzoline plasma concentrations exhibited an apparent biexponential decline following oral absorption. Maximum plasma concentrations and area under the plasma concentration‐time curve increased in proportion to the dose. The mean elimination half‐life among subjects was independent of dose and ranged from 7.3 to 8.7 hours. Oral clearance ranged from 380 to 575 ml/min and was also independent of dose. A single pharmacokinetic equation was used to adequately describe the plasma concentration data over the entire range of doses for each subject, indicating dose‐proportional and linear pharmacokinetics.

BIOAVAILABILITY AND KINETICS OF CIBENZOLINE IN PATIENTS WITH NORMAL AND IMPAIRED RENAL FUNCTION

To test the hypothesis that renal failure alters the disposition of cibenzoline in humans, an absolute bioavailability and elimination kinetic study was performed. We used the simultaneous administration of a stable isotope variant (SASIV). Eight healthy volunteers and eight matched hemodialysis patients each received simultaneously an 80‐mg intravenous infusion of 15N‐2‐cibenzoline and a single 80‐mg cibenzoline capsule. Cibenzoline plasma concentrations were assayed by a gas chromatographic—mass spectrometric assay. A compartment‐independent kinetic analysis showed a plasma clearance of 707 mL/min and an elimination half‐life of 7.3 hours after the intravenous dose in healthy volunteers. In renal‐failure patients, cibenzoline clearance decreased to 224 mL/min and half‐life increased to 22.4 hours. Decreased plasma clearance was due to decreases in both renal and nonrenal clearance. Absolute bioavailability was 83% and 90% in healthy volunteers and renal‐failure patients, respectively. Hemodialysis accounted for only 13% of drug clearance.

Pharmacokinetics of Oral Cibenzoline in Arrhythmia Patients

SummaryThe pharmacokinetics of oral cibenzoline were studied in 30 arrhythmia patients as part of an ascending multiple-dose efficacy study. The elimination half-life of the drug following repetitive dosing ranged from 7.6 to 22.3 hours, with a harmonic mean of 12.3 hours (n = 24), and increased with age and decreasing renal function. The drug exhibited apparent dose proportional and linear pharmacokinetics over the range of doses studied. Multivariate analysis revealed that the patients’ age and serum creatinine concentration accounted for 71% of the variability in the range of β values (terminal elimination rate constant), and that 69.5% of the intersubject variability in the steady-state trough plasma concentrations could be accounted for by the patients’ age, weight and serum creatinine concentration.These data suggest that, although there is some intersubject variability in the elimination and accumulation of cibenzoline, much of the variability can be explained by the patients’ age, weight and renal function.

The influence of liver dysfunction on the pharmacokinetics of carprofen

The pharmacokinetics of the investigational agent carprofen were examined in 12 patients with liver dysfunction (hepatic cirrhosis) and in six normal volunteers following single 100‐mg oral administration of carprofen. In addition, three patients with acute hepatitis received a single 100‐mg dose during the acute phase of the disease, and two of these patients received the same dose after they had convalesced. The pharmacokinetic parameters and urinary excretion data did not differ significantly (P > 0.05) between patients with hepatic cirrhosis and healthy volunteers. The mean ± SD area under plasma concentration‐time curve and apparent oral plasma clearance values were 57.8 ± 11.7 μg × h/mL and 30.0 ± 6.3 mL/min, respectively, in patients and 52.4 ± 11.3 μg × h/mL and 33.1 ± 7.2 mh/min in normals. The respective harmonic mean elimination half‐lives were 10.5 and 9.4 hours. The 0–24 hour urinary recovery of intact drug and the glucuronide conjugate were 7.0 ± 4.9% and 28.9 ± 11.0%, respectively, in patients compared to 5.5 ± 7.1% and 20.1 ± 12.3% in normal subjects. The results of this study showed that liver dysfunction (hepatic cirrhosis) had no effect on the pharmacokinetic profile of carprofen. In the two patients with acute hepatitis who completed the study, the results suggest that the apparent oral clearance of carprofen may increase during the acute phase of the disease.