Gary R. Peters

Steady-state pharmacokinetic properties of pramipexole in healthy volunteers

Pramipexole is a dopamine receptor agonist that has proved effective in the treatment of Parkinsons disease. The pharmacokinetic properties of pramipexole at steady‐state concentrations were studied in 16 healthy men and women at four dose levels throughout the range recommended for Parkinsons patients. Plasma and urine samples collected within the four dose intervals were assayed for concentrations of pramipexole, using high‐performance liquid chromatography. The total oral clearance for all participants was 419 mL/min. The mean volume of distribution and elimination half‐life for all participants was 486 ± 93.2 L and 12.9 ± 3.27 hours. Concentrations of pramipexole were proportional to dose, although the drugs pharmacokinetic properties differed between men and women. The area under the concentration—time curve for each dose level was 35% to 43% greater in women, mainly because of a 24% to 27% lower oral clearance. The mean creatinine clearance in men and women was 112 ± 12.8 mL/min/1.73 m2 and 80.9 ± 15.6 mL/min/1.73 m2, respectively. The renal clearance of pramipexole accounts for approximately 80% of oral clearance, and there was a significant correlation between renal and creatinine clearances. The influence of gender could not be distinguished from the influence of age and the resulting reduced creatinine clearance, but the measurement of pharmacokinetic properties produced linear results in both men and women.

Effect of age and gender on tirilazad pharmacokinetics in humans

Tirilazad mesylate pharmacokinetics were assessed in 12 young and 12 elderly volunteers (six men and six women per age group). Subjects received single 10‐minute intravenous infusions of 1.5 mg/kg and 3.0 mg/kg tirilazad mesylate. Plasma tirilazad mesylate concentrations were determined by HPLC. The were no significant dose effects on clearance, but half‐life increased with dose because of assay insensitivity at the lower dose. Mean half‐lives were 16.3 ± 15.5 and 21.4 ± 12.6 hours for young and elderly subjects, respectively, at the 3.0 mg/kg dose. At the same dose, mean tirilazad mesylate systemic clearance was 0.630 ± 0.254 and 0.428 ± 0.090 L/hr/kg, respectively. The decreased clearance in elderly volunteers was primarily attributable to a lower clearance in elderly women relative to young women. The small effect of age on tirilazad clearance is likely to have minimum clinical impact. Tirilazad clearance was approximately 40% higher in young women than in young men. The clinical importance of this observation is unknown.

Evaluation of the Pharmacokinetics and Tolerability of Tirilazad Mesylate, a 21-Aminosteroid Free Radical Scavenger: I. Single-Dose Administration

The single‐dose tolerability and pharmacokinetics of tirilazad mesylate, a 21‐aminosteroid free radical scavenger, were assessed in 47 healthy male subjects. Subjects were randomized to receive citrate vehicle (n = 12) or 0.25 mg/kg (n = 9), 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 8), or 2.0 mg/kg (n = 9) tirilazad mesylate by 0.5‐hour intravenous infusion. Injection site pain was observed with approximately equal frequency in both vehicle and tirilazad mesylate treatment groups. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, liver enzymes, or renal function were apparent. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol eosinophil, or lymphocyte levels). Maximal plasma concentrations of tirilazad mesylate increased linearly with dose. Limited assay sensitivity at the lower two doses prevented determination of the dose proportionality of tirilazad area under the curve. The apparent elimination half‐life at the higher doses was 3.7 hours. Clearance of tirilazad mesylate approached liver blood flow. Results indicate that intravenous infusions at these doses are well tolerated and devoid of glucocorticoid effects. Tirilazad mesylate appears to be efficiently cleared by the liver, and its pharmacokinetics are apparently linear over the dosage range studied.

Effect of Gender and Menopausal Status on the Pharmacokinetics of Tirilazad Mesylate in Healthy Subjects.

The pharmacokinetics of tirilazad were assessed in men ages 40--60 years, women <40 years of age, premenopausal women ages 40--60, and postmenopausal ages 40--60. Eight subjects in each group received single 3.0 mg kg(minus sign1) intravenous infusions of tirilazad mesylate over 10 min. Plasma concentrations of tirilazad and U-89678, an active metabolite, were measured by high-performance liquid chromatography. Tirilazad administration was well tolerated in all groups. Mean tirilazad clearance was 59.6% higher in young women compared to the middle-aged men (35.6 plus minus 8.04 L h(minus sign1) vs. 22.3 plus minus 8.40 L h(minus sign1)). Mean tirilazad clearance in middle-aged women was 30.7% higher than in middle-aged men. Mean clearance in postmenopausal women (26.1 plus minus 4.21 L h(minus sign1)) was not significantly different than that in middle-aged men, but clearance corrected for body weight was significantly different between the men and postmenopausal women. Clearance in premenopausal middle-aged women (32.2 plus minus 7.60 L h(minus sign1)) was not significantly different from that in young women and was 44% greater than that in middle-aged men. Mean AUC(0minus signinfty infinity) and C(max) values for U-89678 were significantly higher in men than in all of the female groups. Among the women, values for U-89678 AUC(0minus signinfty infinity) were lowest in young women (467 plus minus 345 ng h ml(minus sign1), 8.8% of male value) and highest in postmenopausal women (1565 plus minus 1382 ng h ml(minus sign1), 29.4% of male value). The absolute values for U-89678 AUC(0minus signinfty infinity) must be interpreted with caution, as limited assay sensitivity and low plasma concentrations in the latter portion of the concentration-time profile in women precluded accurate determination of the terminal half-life and AUC(0minus signinfty infinity). Regardless, these results show that women, particularly premenopausal women, have lower concentrations of U-89678, an active metabolite of tirilazad, than are achieved in men. The gender differences in tirilazad and U-89678 pharmacokinetics are of sufficient magnitude that they may impact the clinical response of male and female patients to tirilazad treatment.

Gender does not affect the degree of induction of tirilazad clearance by phenobarbital.

Abstract.Objective: Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F).Methods:Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg⋅kg−1 tirilazad mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC.Results:Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC0–6 for U-89678 after the last tirilazad mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction.Conclusion:The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response.

Influence of probenecid (PR) and cimetidine (C) on pramipexole (PX) pharmacokinetics

Clinical Pharmacology & Therapeutics (1996) 59, 183–183; doi: 10.1038/sj.clpt.1996.233

The effect of phenytoin on the pharmacokinetics of tirilazad mesylate in healthy male volunteers

The pharmacokinetic interaction between phenytoin and tirilazad was studied in 12 healthy men who received 200 mg phenytoin orally every 8 hours for 11 doses and 100 mg for the remaining 5 doses in one period of a two‐way crossover study. In both periods, 1.5 mg/kg tirilazad mesylate was administered (as 10‐minute intravenous infusions) every 6 hours for 21 doses (5 days). Plasma tirilazad mesylate and U‐89678 (an active metabolite) were quantified by HPLC. After dose 21, area under the plasma concentration‐time curve [AUC(0–6)] for tirilazad mesylate was significantly lower (p = 0.0061) after phenytoin treatment (3029 ± 982 ng · hr/ml) than after tirilazad mesylate alone (4647 ± 1562 ng · hr/ml). AUC(0–6) for U‐89,678 after dose 21 was reduced from 1485 ± 1173 ng · hr/ml after tirilazad mesylate alone to 195 ± 223 ng · hr/ml after phenytoin coadministration. U‐89678 normally accumulates during multiple dosing, but mean U‐89678 trough concentrations decreased after 24 hours during tirilazad and phenytoin coadministration. No clinically significant interactions of tirilazad mesylate and phenytoin for medical events, vital signs, or laboratory parameters were identified. These results suggest that phenytoin rapidly induces tirilazad mesylate metabolism; it may also induce the metabolism of U‐89678 or shunt tirilazad mesylate metabolism through other pathways.

Influence of age and gender on pramipexole (PX) pharmacokinetics

Clinical Pharmacology & Therapeutics (1996) 59, 184–184; doi: 10.1038/sj.clpt.1996.234

Cardiovascular and hormonal effects of pramipexole, a novel dopamine agonist

Clinical Pharmacology & Therapeutics (1996) 59, 178–178; doi: 10.1038/sj.clpt.1996.210

Lack of a Pharmacokinetic/Pharmacodynamic Interaction Between Nimodipine and Tirilazad Mesylate in Healthy Volunteers

The potential interaction between tirilazad mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium‐channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad mesylate as a 10‐minute intravenous infusion, and a combination of the two treatments according to a balanced 3‐way crossover design. No significant effects of nimodipine on tirilazad mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad mesylate clearance (34.9 ± 8.96 L/hr) and half‐life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad mesylate and nimodipine is detectable after single‐dose administration.