Single rising dose studies

The results of these studies in patients and subjects t ng carbamazepine long term differ from single-dose studies and short-term studies in healthy subjects. For example, a 33% rise in serum carbamazepine levels, a 20% fall in clearance and a 26% increase inthe AUC have been reported, which would indicate that there is some potential for a clinically significant interaction (see Mechanism below). 

Single-dose studies into the renal exeretion of amantadine in healthy sub-jeets found that quinine sulfate 200 mg and quinidine sulfate 200 mg re-dueed the renal clearance of oral amantadine 3 mg/kg by about 30%, but only in male subjects. Whether long-term use of these drugs would therefore eause a clinically relevant rise in serum amantadine levels is uncertain. However, the absenee of any elinieal reports suggests it is unlikely. 

A single-dose study in 8 cocaine addicts found that there was a dose-de-pendent rise in cocaine levels of 6%, 49% and 67% after clozapine was given in doses of 12.5,25 or 50 mg, respectively, with intranasal cocaine 2 mg/kg. Subjective questioning revealed a reduction in the positive effects of cocaine. One subject also experienced a near-syncopal attack which required medical attention.- ... 

These findings contrast with those of a 6-week study, in which 6 out of 7 schizophrenics had 15 to 122% rises in their plasma haloperidol levels when they were given buspirone. The authors also mention a single-dose study in healthy subjects, which found a 30% rise in haloperidol levels when subjects were given buspirone. ... 

The AUC of amprenavir was inereased by 32% in one study, but in another, the pharmaeokineties of amprenavir were not affected when ketoconazole was given with fosamprenavir/ritonavir. In a single-dose study amprenavir 1.2 g caused a 44% rise in the AUC of ketoconazole 400 mg. Similarly, the AUC of ketoconazole was increased by 2.7-fold by fosam-prenavir/ritonavir. ... 

A rise in digoxin levels of about 50% was seen in chronic haemodialysis patients given verapamil 120 to 240 mg daily.Nine healthy subjects had a 53% rise in their digoxin levels while taking verapamil 240 mg three times daily for two weeks. Toxicity and a fatality occurred in patients whose digoxin levels became markedly increased by verapamil. Both asystole and sinus arrest have been described. " A single-dose study indicated that cirrhosis magnifies the extent of this interaction. ... 

The effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of atorvastatin, ceri-vastatin, and pravastatin have been evaluated in an open, randomized, crossover study in 18 healthy subjects who took single doses of atorvastatin 20 mg, cerivastatin 0.8 mg, or pravastatin 40 mg, with and without itraconazole 200 mg (72). Itraconazole markedly raised atorvastatin plasma concentrations (2.5-fold) and produced modest rises in the plasma concentrations of cerivastatin (1.3-fold) and pravastatin (1.5-fold). These results suggest that in patients taking itraconazole, cerivastatin or pravastatin may be preferable to atorvastatin. 

Clinical study demonstrated a steady plasma level throughout the day after dosing of a single 60-mg dose with elimination of the rapid rise in plasma concentration seen with IR dosing (20 mg nifedipine administered three times a day) as shown in Figure 22.8. The study also showed that the product was well tolerated with an improved safety proLle. 

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