Diane K. Jorkasky

Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers

To investigate the effect of steady‐state fluconazole administration on the disposition of eprosartan, losartan, and E‐3174.

Urinary excretion of 6β-hydroxycortisol as an in vivo marker for CYP3A induction : Applications and recommendations

To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development.

Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure

Carvedilol is a relatively new drug with β‐and α1‐receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple‐dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(−)‐carvedilol, R(+)‐carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice‐daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose‐proportional increases in steady‐state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady‐state plasma concentrations of the active metabolites also increased in a dose‐proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25–50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.

Use of topical corticosteroid pretreatment to reduce the incidence and severity of skin reactions associated with testosterone transdermal therapy

Local skin reactions at the application site are the most common adverse events associated with the testosterone transdermal delivery (TTD) systems used to treat postpubertal hypogonadism in males. This open-label, controlled pilot study was conducted to determine whether topical pretreatment with triamcinolone acetonide 0.1% cream might be useful in reducing the incidence and/or severity of chronic skin irritation when used in healthy volunteers receiving TTD systems. Adult male volunteers wore three topical systems, which were applied to the upper back daily (Monday through Friday) for 6 weeks: (1) TTD with no pretreatment of application site; (2) TTD with pretreatment of application site using triamcinolone acetonide 0.1% cream; and (3) an inactive occlusive dressing (control). On Monday through Thursday, systems were removed 24 hours after application. Patches applied on Friday were worn continuously for 72 hours until their removal on Monday. Skin reactions were graded on a scale from 0 to 4 (0 = none, 4 = severe) and were assessed daily by research personnel, beginning at the time of system removal (assessment 1) and on the two subsequent clinic visits (assessments 2 and 3). All skin irritation scores of all subjects were totaled for each treatment regimen to obtain a cumulative score per treatment regimen. The cumulative scores were also analyzed by assessment time and study week (weeks 1-6). Eighty-two subjects were enrolled in the study, and 65 completed the 6-week treatment course. Mean age of subjects was 24 years (range, 18-69 years), and mean weight was 79.0 kg (range, 58.9-127.3 kg). All subjects were white males. At assessment 1, pretreatment with triamcinolone acetonide 0.1% cream (compared with no pretreatment) was associated more often with scores of 0 (no erythema), with comparable occurrences of mild skin irritation, and with fewer occurrences of moderate erythema. At all three assessments, more subjects had lower cumulative scores with pretreatment than without pretreatment. At every assessment and in each week of the study, total weekly cumulative skin irritation scores were also lower with pretreatment than without pretreatment. No adverse experiences other than skin irritation were reported. Results of this study suggest that in patients using TTD systems, the incidence and severity of skin irritation at application sites may be reduced through pretreatment with triamcinolone acetonide 0.1% cream.

Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban

Argatroban, a direct thrombin inhibitor, is metabolized in vitro by CYP3A4/5 and therefore may be susceptible to clinically relevant CYP3A drug interactions. The effect of erythromycin, a potent CYP3A4/5 inhibitor, on the pharmacokinetics and pharmacodynamics of argatroban was evaluated in 14 healthy male volunteers in an open‐label, crossover study with a 5‐day washout between regimens. Argatroban 1 μg/kg/min was infused alone for 5 hours (regimen A) and again on day 6 of a 7‐day oral regimen of 500 mg erythromycin four times daily (regimen B). Serial blood samples for the determination of activated partial thromboplastin time (aPTT) and argatroban concentrations were collected for up to 48 hours following infusion. Mean values for argatroban area under the concentration‐time curves (AUC0 — inf), maximum concentration (Cmax), and half‐life (t1/2) were similar between regimens. Mean aPTT values were not affected significantly by the concomitant administration of argatroban and erythromycin compared to argatroban alone. No serious adverse events or bleeding episodes occurred during the study. These results suggest that oxidative metabolism by CYP3A4/5 is unlikely to be an important in vivo elimination pathway for argatroban. Therefore, coadministration of CYP3A4/5 inhibitors should not require a modification in the dosage of argatroban.

Systemic exposure to rosiglitazone is unaltered by food

AbstractObjective: To evaluate the effect of food on the bioavailability and pharmacokinetics of the insulin sensitizer rosiglitazone. Methods: In a randomized, open-label, period-balanced, single-dose, crossover study, rosiglitazone 2 mg was administered to 12 healthy male volunteers either in the fasting state or following a standard high-fat breakfast. The primary end points of the study were AUC0–inf and Cmax. Results: Single oral doses of rosiglitazone were safe and well tolerated. Overall exposure to rosiglitazone was unaffected by food. The geometric mean ratio of AUC(0–inf) in the fed:fasted regimens was 0.94 (95% CI: 0.82, 1.06); t1/2 was unaffected. Absorption of rosiglitazone in the fed state was more gradual and sustained than in the fasted state. Cmax was reduced by approximately 20% (point estimate 0.80; 95% CI 0.65 to 0.97) and tmax was modestly delayed in the fed state. Conclusion: These data support dosing guidelines that will permit the administration of rosiglitazone without regard to meals for treatment of type 2 diabetes mellitus.

Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment

To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment.

Pharmacokinetics and Protein Binding of Eprosartan in Healthy Volunteers and in Patients with Varying Degrees of Renal Impairment

This was an open‐label, parallel group study to compare the pharmacokinetics of multiple oral doses of eprosartan in subjects with normal renal function (Clcr >80 mL/min; n = 8) and patients with mild (Clcr 60–80 mL/min; n = 8), moderate (Clcr 30–59 mL/min; n = 15), or severe (Clcr <30 mL/min; n = 3) renal insufficiency. Each subject received oral eprosartan 200 mg twice daily for 6 days and a single dose on day 7. Mean total maximum concentration (Cmax) and area under the concentration—time curve from 0 to 12 hours (AUC0–12) were similar for healthy subjects and those with mild renal impairment, but were an average of 25% to 35% and 51% to 55% greater for patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Mean renal clearance (Clr), which was similar for healthy subjects and patients with mild renal impairment, was decreased an average of 41% and 95% in the groups with moderate and severe renal impairment, respectively, compared with normal subjects. Eprosartan was highly bound to plasma proteins in all groups; however, the unbound fraction was increased approximately two‐fold in the group with severe renal impairment. Mean unbound Cmax and AUC0–12 were an average of 53% to 61% and 185% to 210% greater for the patients with moderate and severe renal impairment, respectively, compared with healthy subjects. Headache was the most common adverse experience reported in all subgroups. Eprosartan was safe and well tolerated regardless of degree of renal impairment. Cmax and AUC were increased and renal clearance decreased in patients with moderate to severe renal impairment in comparison to healthy subjects and patients with mild renal impairment. However, based on the moderate renal clearance and known safety profile of eprosartan, it is not necessary to adjust the dose of eprosartan in patients with renal insufficiency.

Pharmacokinetics of Testosterone in Hypogonadal Men After Transdermal Delivery: Influence of Dose

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 ± 10.5 years) were enrolled in an open‐label, randomized, crossover study. Each application period comprised 4 days: a 2‐day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patients back. On day 4 of each period, serial blood samples were collected for determination of total and non‐sex hormone binding globulin (non‐SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration—time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non‐SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.

Comparative Effects of Nabumetone, Sulindac, and Indomethacin on Urinary Prostaglandin Excretion and Platelet Function in Volunteers

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side‐effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21–43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period‐balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6‐keto‐PGF1α, PGF2α, thromboxane [TX] B2) and platelet function (collagen‐induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2α, but 6‐keto‐PGF1α and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6‐keto‐PGF1α and TXB2 excretion rates. Reduced excretion of PGF2α was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6‐keto‐PGF1α excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2α excretion and between the NAB and SUL regimens for PGE2, PGF2α, 6‐keto‐PGFα1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6‐keto‐PGF1α, suggests that NAB possesses renal sparing properties.