Thalomid Pharmacology, Pharmacokinetics, Studies, Metabolism - Thalidomide

Thalomid Pharmacology, Pharmacokinetics, Studies, Metabolism - Thalidomide

CLINICAL PHARMACOLOGY

Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood.

Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration.^3-6 For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL,³ however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients.⁷

Absorption : The absolute bioavailability of thalidomide from THALOMIDÒ (thalidomide) capsules has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) of THALOMIDÒ (thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMIDÒ (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 1 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Coadministration of THALOMIDÒ (thalidomide) with a high fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.

Distribution : In human blood plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide.⁸ In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.

Metabolism : At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. In a repeat dose study in which THALOMIDÒ (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism.

Elimination : As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number of metabolites,⁹ only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was identified in the urine of subjects 12 to 24 hours after dosing.

HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single dose administration of THALOMIDÒ (thalidomide) capsules.

Patients with Hansen’s Disease: Analysis of data from a small study in Hansen’s patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMIDÒ (thalidomide). The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.

Patients with Renal Insufficiency: The pharmacokinetics of thalidomide in patients with renal dysfunction have not been determined.

Patients with Hepatic Disease: The pharmacokinetics of thalidomide in patients with hepatic impairment have not been determined.

Age: Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen’s disease ranging in age from 20 to 69 years does not reveal any age-related changes.

Pediatric: No pharmacokinetic data are available in subjects below the age of 18 years.

Gender: While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.

Race: Pharmacokinetic differences due to race have not been studied.

The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.

Waters¹² reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.

Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.

Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.

3. Sampaio EP, Kaplan G, Miranda A, et al. 1993. J. Infect. Dis. 168(2):408-414.

4. Sarno EN, Grau GE, Vieira LM, et al. 1991. Clin. Exp. Immunol. 84:103-108.

5. Sampaio EP, Moreira AL, Sarno EN, et al. 1992. J. Exp. Med. 175:1729-1737.

6. Nogueira AC, Neubert R, Helge H, et al. 1994. Life Sciences. 55(2):77-92.

7. Jacobson JM, Greenspan JS, Spritzler J, et al. 1997. New Eng. J. Med. 336(21):1487-1493

8. Eriksson T, Bj rkman S, Roth B, et al. 1998. Chirality. 10(3): 223-228.

9. Schumaker H, Smith RL, and Williams RT. 1965. Br. J. Pharmacol. 25:324-337.

10. Iyer CGS, Languillon J, Ramanujam K, et al. 1971. Bull. WHO. 45:719-732.

11. Sheskin J and Convit J. 1969. Intl. J. Leprosy. 37:135-146.

12. Waters MFR. 1971. Lepr. Rev. 42:26-42.

13. Unpublished data, on file at Celgene.