Aims To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildena®l (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, 320. Methods Three open-label, parallel-group studies were conducted. The ®rst study compared sildena®l pharmacokinetics, safety and toleration in 15 healthy young male subjects (mean age 30 years; range 19±45 years) to 15 healthy elderly male subjects (mean age 70 years; range 65±81 years). The second study included eight male volunteers with normal renal function and 16 male volunteers with varying degrees of renal impairment as assessed by measurement of creatinine clearance (CL cr ). The third study included 12 male volunteers with normal hepatic function and 12 male volunteers with chronic stable hepatic cirrhosis (Child-Pugh A and B). For all three studies, blood and urine samples were collected predose and at speci®ed intervals up to 48 h postdose for assays of sildena®l and UK-103,320, and measurements of protein binding. Results Signi®cant differences in C max and AUC were observed between the young and the elderly subjects for both the parent drug and the metabolite. In the elderly, AUC values were approximately twice as high and C max values 60±70% higher than those for young men, while t 1/2 values were approximately 1 h longer for sildena®l and 2 h longer for UK-103,320. Due to a signi®cantly smaller unbound fraction of drug in the elderly, free drug concentrations were only approximately 40% higher in the elderly group compared to the young group. In the renal impairment study, signi®cant correlations with CL cr were demonstrated for sildena®l oral clearance (CL/F) and C max and UK-103,320 C max and AUC. Pairwise comparisons between subjects with normal renal function and those with severe renal impairment (CL cr <30 ml min x1 ) supported these ®ndings, showing signi®cant increases in C max and AUC for both the parent drug and the metabolite in the severely impaired subjects. The hepatic impairment study demonstrated that the pharmacokinetics of sildena®l were altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in C max compared with subjects with normal hepatic function, suggesting a reduction in ®rst-pass metabolism as well as systemic clearance. The increase in systemic exposure for UK-103,320 was approximately twice that seen for the parent drug. In all three studies, sildena®l was well tolerated, most adverse events were mild and no subjects discontinued treatment. Conclusions Sildena®l pharmacokinetics were affected by age and by renal and hepatic impairment, suggesting that a lower starting dose of 25 mg should be considered for patients with severely compromised renal or hepatic function.

Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200 mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (C(max)) of 1-2 mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC( infinity )) of 18 mg. h/L, apparent elimination half-life of 6 hours and apparent systemic clearance of 10 L/h. Thalidomide pharmacokinetics are best described by a one-compartment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacokinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than its absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state C(max) (C(ss)(max)) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with C(ss)(max) of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400 mg. Because of the low solubility of thalidomide, C(max) is less than proportional to dose, and t(max) is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function.

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