PHA5128 Dose Optimization II Case Study I Spring 2013

Transcription

1 Silsamicin is an investigational compound being evaluated for its antimicrobial effect. The route of administration for this drug is via intravenous bolus. Approximately 99.9% of this drug is eliminated by the kidney. Tubular secretion and reabsorption do not play a role in the elimination of this drug. Silsamicin has no plasma protein binding. Assuming ideal body weight for both individuals, compute the clearance of silsamicin for the following individuals: (1) Male, 45 years of age, 180 lbs with serum creatinine of 1.9 mg/dl (2) Female, 60 years of age, 130 lbs with serum creatinine of 3.7 mg/dl 1

2 The blood samples of ABC13245 were obtained after an intravenous bolus administration of 100 mg ABC The pharmacokinetic profile follows a biexponential decline. The data was fitted to a bi-exponential decay equation and the following intercepts and rate constants were obtained: Compute its CL, V ss and MRT. The clinical peak is defined as the concentration of the drug in the plasma 30 minutes after the end of administration. The clinical trough is the concentration 30 minutes prior to the next administration. Assume that the dosing interval is 12 hour. Compute the clinical peak and trough concentrations of ABC Use the following additional equations for your computation: First we determine the area under the curve and area under the moment curve: CL can be determined such that: The approximate clinical peak concentration, given that the drug was administered as an IV bolus, is the concentration at 0.5 hour: The estimated clinical trough concentration is the drug concentration at 11.5 h: 2

3 Drug A is administered as a racemic mixture. If the clearance of the R-isomer is 70 ml/min whereas the clearance of the S-isomer is 50 ml/min and change in urine flow has no effect on the renal clearance of either isomer, explain the difference in renal clearance of the two isomers. Given that the renal clearance is unchanged when urine flow changes, tubular reabsorption does not appear to play a role for the two isomers. A renal clearance below 100 ml/min (GFR) implies significant plasma protein binding. The likely mechanism for the difference in the renal clearance of the two isomers is stereoselective plasma protein binding. 3

4 Assuming that drug A exhibited a total clearance of 2.48 L/h. Its elimination is 70% hepatic metabolism and 30% renal excretion. No significant plasma protein binding was reported for Drug A. Drug A has a narrow therapeutic window. If drug C that reduces the intrinsic clearance of Drug A by 25% is added to the drug regimen of the patient receiving a constant infusion of drug A, would you change the infusion rate of drug A in this patient? We compute the actual hepatic clearance: To determine if the hepatic clearance is low or high intrinsic clearance, compared to the hepatic blood flow (1.0 to 1.5 L/min), we convert the hepatic clearance to the same unit: This is a low intrinsic clearance drug. By decreasing the intrinsic clearance by 25%, you will decrease the total clearance and C ss will increase. Since no significant plasma protein binding was known for Drug A, the free drug that exerts the pharmacological effect is the same as C ss. The infusion rate should be reduced when drug C is co-administered. 4

5 When drug C is co-administered to patients receiving drug A, the average Css of drug A decreases. No change in the pharmacologic action was observed. Explain why this is the case. A decrease in the average C ss without a change in the pharmacologic effect implies that the free drug concentration remained unchanged. This is often observed with protein binding displacement with low intrinsic clearance drugs. Thus, drug A is likely a low intrinsic clearance drug. Using the following equation: For low intrinsic drug,, thus As the f u (fraction unbound) increases, the CL increases, resulting in a decrease in C ss, However, free C ss remained unchanged. 5