Michael D. Karol

Effects of passive smoking on theophylline clearance

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long‐term exposure to cigarette smoke, and seven age‐matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48‐hour postinfusion period. Clearance for passive smokers was 6.01 × 10−2 L/hr · kg and for nonsmokers, clearance was 4.09 × 10−2 L/hr · kg (p < 0.025). Terminal elimination half‐life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p < 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p < 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p < 0.004) and urine (p < 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p < 0.01) and urine (r = 0.79, p < 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.

Effect of Phenytoin on the Clinical Pharmacokinetics of Amiodarone

Five healthy male volunteers were given oral amiodarone hydrochloride, 200 mg per day for 6½ weeks, to determine its effects on the pharmacokinetics of both intravenous and oral phenytoin. Predose amiodarone and N‐desethylamiodarone serum concentrations were obtained weekly during weeks 2–6. Amiodarone serum concentrations (ASC) increased during weeks 2–4 and then decreased sharply during weeks 5–6 when oral phenytoin, 2–4 mg/kg/day, was co‐administered. In addition, N‐desethylamiodarone serum concentrations (DEASC) exceeded corresponding ASC during weeks 5–6 whereas during weeks 2–4, DEASC were less than ASC. Because of the long elimination half‐life for amiodarone previously reported in healthy volunteers after single doses of amiodarone and the frequent administration of amiodarone associated with this half‐life, a modified equation for a continuous infusion was used to describe each subjects ASC versus time data. Pre‐phenytoin ASC were fitted to an appropriate function to predict ASC during weeks 5–6 assuming no interaction. Observed versus predicted ASC were compared for weeks 5 and 6. Observed ASC during weeks 5 and 6 were (mean ± SD) 0.25 ± 0.09 μg/mL and 0.19 ± 0.07 μg/mL, respectively. Corresponding predicted ASC were 0.36 ± 0.12 μg/mL (P = .011) and 0.38 ± 0.13 μg/mL (P = .004). These represented percent differences of 32.2 ± 12.5% and 49.3 ± 5.6% for weeks 5 and 6, respectively. Assuming there were no changes in the bioavailability of amiodarone during continuous administration, these findings strongly suggest induction of amiodarone metabolism by phenytoin. The clinical significance of this interaction remains to be determined.

Metabolite Formation Pharmacokinetics: Rate and Extent of Metabolite Formation Determined by Deconvolution

A two-step analytic procedure to determine the rate and extent of metabolite production following administration of the parent compound is described. The procedure provides the rate and extent of metabolite production as a function of time by application of the general model independent approach of deconvolution. The metabolite unit impulse response function is obtained by implicit deconvolution of the metabolite data with a truncated constant-rate metabolite input function. Then the obtained unit impulse response function is used in an analytic deconvolution with metabolite data following administration of the parent compound to obtain the rate and extent of metabolite production. The input function is also deconvolved with metabolite data to obtain the unit impulse response function appropriate for prediction of metabolite levels given a selected input of parent compound. The expected profile following administration of the consecutive infusions of parent drug is shown for both parent and metabolite. The rationale for selection of deconvolution methods is discussed. The approach is applied to data for procainamide and N-acetylprocainamide from three human subjects. The results indicate that from 27 to 39% of the procainamide was converted to N-acetylprocainamide in these subjects.

Lansoprazole pharmacokinetics in subjects with various degrees of kidney function

The pharmacokinetics of lansoprazole, a new benzimidazole proton pump inhibitor, was evaluated after multiple‐dose oral administration to 20 subjects with various degrees of kidney function. Multiple blood samples were obtained after doses 1 and 7 of the once‐daily seven‐dose regimen, and plasma concentrations of lansoprazole and five metabolites were quantitated with use of HPLC. The free fraction of lansoprazole increased as kidney function declined. A significant, although weak, relationship existed between creatinine clearance (CLCR) and area under the plasma concentration versus time curve (AUC) and terminal disposition half‐life (t½), calculated with total concentration data. Those individuals with lower CLCR values also had lower total AUC and t½ values. However, there was no statistically significant relationship between CLCR and peak plasma concentration or AUC, calculated with unbound concentration data. No adjustment of lansoprazole dose is recommended on the basis of impaired kidney function.

Lack of Pharmacokinetic Interaction between Lansoprazole and Intravenously Administered Phenytoin

The objective of this randomized, double‐blind, two‐period crossover study was to investigate whether concomitant steady‐state lansoprazole influences the pharmacokinetics of CYP2C9 substrates using single intravenously dosed phenytoin as a model substrate. In addition, the safety of concomitant administration of these two drugs was evaluated. Twelve healthy, nonsmoking, adult male subjects received 60 mg lansoprazole or placebo once daily for 9 days during each study period. On the morning of day 7, each subject received a single 250 mg intravenous phenytoin dose. There were no statistically significant differences between the two regimens for mean phenytoin Cmax or tmax. There was a minor (< 3%) but statistically significant difference between the two regimens for phenytoin AUC resulting from a very low intrasubject coefficient of variation (2.3%). The treatment and control mean plasma concentration phenytoin profiles were virtually super‐imposable. In conclusion, concomitant multidose lansoprazole administration is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2C9 substrates in general or intravenous phenytoin specifically.

Lack of pharmacokinetic interaction after administration of lansoprazole or omeprazole with prednisone

In a recently reported case, administration of omeprazole, a “proton pump” inhibitor, was temporally associated with the clinical relapse of pemphigus in a 44‐year‐old woman whose condition had been stabilized with a fixed dose of prednisone, suggesting the possibility of a drug interaction. This placebo‐controlled, randomized, double‐blind, three‐period crossover study was conducted to evaluate and compare the pharmacokinetics of prednisolone after a single dose of prednisone given during multi‐dose administration of lansoprazole or omeprazole. Lansoprazole (30 mg), omeprazole (40 mg), or placebo was administered once daily under fasted conditions for 7 days to healthy male volunteers. On the seventh day, a single dose of prednisone (40 mg) was administered concomitantly with the study medication, and plasma prednisolone concentrations were measured by high‐performance liquid chromatography for 24 hours thereafter. Two weeks separated the first doses of each study period. Eighteen volunteers entered the study; pharmacokinetic data were evaluable for 15 participants. Safety data were evaluable for 16 participants in the lansoprazole/prednisone group; 17 in the omeprazole/prednisone group; and 17 in the placebo/prednisone group. The pharmacokinetic parameters for prednisolone, including the maximum observed plasma concentration (Cmax), time to maximum plasma concentration (tmax), terminal‐phase half‐life (t1/2), and area under the concentration—time curve, were comparable for the three regimens. Adverse events (AEs) rated as possibly or probably drug related were reported by 50%, 24%, and 47% for subjects in the lansoprazole, omeprazole, and placebo treatment groups, respectively. Headache was the most common drug‐related AE. No serious AEs were reported, and no subject withdrew from the study because of an AE. Concomitant administration of lansoprazole or omeprazole does not affect the absorption, biotransformation, or disposition of a single dose of prednisone. All three treatment regimens were well tolerated.

Pharmacokinetics of Lansoprazole in Hemodialysis Patients

The pharmacokinetics of the new benzimidazole proton pump inhibitor lansoprazole and five of its metabolites were assessed after single oral dose administration to five hemodialysis patients. Patients were studied on dialysis and nondialysis days. Multiple blood and dialysate samples were collected after dosing and were assayed for lansoprazole and metabolite content via high‐performance liquid chromatography. The degree of lansoprazole plasma protein binding was lower in hemodialysis patients than in subjects with normal renal function or patients with renal impairment not requiring dialytic therapy, although this tended to moderate when assessed immediately after dialysis. Examination of venous plasma concentration, paired arterial‐venous concentration, and dialysate data revealed that lansoprazole and its metabolites were poorly dialyzable. No dosage adjustment of lansoprazole is necessary in hemodialysis patients nor is supplementation after hemodialysis sessions necessary.

Lack of interaction between lansoprazole and propranolol, a pharmacokinetic and safety assessment.

Due to the prevalence of both gastrointestinal and cardiovascular diseases, it is likely that patients may be coprescribed gastric parietal cell proton pump inhibitors and beta‐adrenergic antagonists. Therefore, the objectives of this phase I study were to assess the potential effects of the coadministration of lansoprazole on the pharmacokinetics of propranolol and to evaluate the safety of propranolol with concomitant lansoprazole dosing. In a double‐blind fashion, 18 healthy male nonsmokers were initially randomized to receive either 60 mg oral lansoprazole, each morning for 7 days, or an identical placebo (period 1). On day 7, all subjects were concomitantly administered oral propranolol, 80 mg. After a minimum of 1 week following the last dose of either lansoprazole or placebo, subjects were crossed over to the opposite treatment for another 7 days (period 2). Subjects were again administered oral propranolol on day 7. During both treatment periods, blood samples for the determination of plasma propranolol and 4‐hydroxy‐propranolol were obtained just before the dose and at 0.5, 1, 2, 3, 4, 6, 8 12, 16, 20, and 24 hours postdose. Plasma propranolol and 4‐hydroxy‐propranolol concentrations were determined by using HPLC with fluorescence detection. The Cmax, tmax, AUCQ0‐∞, and t1/2 values for propranolol, as well as the AUC0‐∞ for 4‐hydroxy‐propranolol, were calculated and compared between the lansoprazole and placebo regimens. The mean age of the 15 subjects who successfully completed the study was 31 years (range: 24–38 years), and their average weight was 174.8 pounds (range: 145–203 pounds). There were no statistically significant differences between the lansoprazole and placebo regimens for the propranolol Cmax, tmax, AUC0‐∞, and t1/2 values. Also, there were no statistically significant differences between regimens for the 4‐OH‐propranolol AU0‐∞. Safety evaluations, which included adverse events, vital signs, clinical laboratory determinations, ECG, and physical examinations, revealed no unexpected clinically significant findings and did not suggest a drug‐drug interaction. In conclusion, lansoprazole does not significantly alter the pharmacokinetics of propranolol, suggesting that it does not interact with the CYP2D6‐ or CYP2C19‐mediated metabolism of propranolol. Modification of a propranolol dosage regimen in the presence of lansoprazole is not indicated, based on the pharmacokinetic analysis and the lack of a clinically significant alteration in the pharmacodynamic response.