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A number of drugs can inhibit the metabolism of other drugs. An example is the 1998 withdrawal from the market of the drug mibefradil (Posicor®). Shortly after the 1997 FDA approval of this drug it was found to be a potent metabolic inhibitor of drugs such as simvastin and other statins, cyclosporin and terfenadine resulting in serious toxicities. Warfarin inhibits tolbutamide elimination which can lead to the accumulation of drug and may require a downward adjustment of dose. Grapefruit juice has been shown to cause a two-fold increase in saquinavir AUC and reduced (inhibited) metabolism of other drugs such as midazolam and coumarin.
Carbamazepine is a drug which can induce its own metabolism during the first few days of therapy (Hawkins Van Tyle and Winter, 2004). After the first dose, carbamazepine pharmacokinetic parameters include F = 0.8, V = 98.0 L, CL = 1.75 L/hr (estimate for 70 Kg subject). After 3 to 5 days carbamazepine metabolism is induced such that the CL becomes 4.48 L/hr. Pre-induction (first-dose) parameter values are kel = 0.0179 hr-1 and V = 98 L. After induction the kel changes to 0.0457 hr-1. Dose adjustment during the first few days can be difficult. Using post induction parameters for initial dosage regimen could cause toxic concentrations. For example, try the simulation again with a dose regimen of 600 mg every 12 hours with both pre and post induction kel values. The typical therapeutic plasma concentration range is 4 - 12 mg/L. Explore the problem as a Linear Plot - Interactive graph.
Item 2. Theophylline has been studied extensively. It has been used commonly and has been the subject of therapeutic drug monitoring (TDM) because of its variable pharmacokinetic parameters and narrow therapeutic window. Theophylline parameter values vary considerably with disease state, enyzme status (drug co-administration or smoker status) and formulation factors.
Theophylline is marketed in a number of oral dosage forms. Rapid release tablets generally are rapidly and completely absorbed with F close to 1.0 and ka values above 2 hr-1. The apparent volume of distribution is approximately 0.5 L/Kg (ideal body weight, IBW). Average values of theopylline clearance approximate 0.04 L/Kg/hr (based on IBW). A number of factors can influence this average clearance value. For example; smoking x 1.6, cimetidine co-administration x 0.6, phenytoin co-administration x 1.6, congestive heart failure x 0.5 (depending on status), cystic fibrosis x 1.5, hepatic cirrhosis x 0.5. Considering a 70 Kg (IBW) non-smoker patient the expected V and kel might be 35 L and 0.08 hr-1. For a patient that smokes the kel would be expected to be approximately 0.125 hr-1. Try adjusting the parameter values according to these covariates and adjust the dosing regimen to maintain appropriate therapeutic concentrations. Currently, the therapeutic window ranges from 5 to 20 mg/L whereas earlier a range of 10 to 20 mg/L had been used. Average plasma concentration targets includes values around 10 mg/L or in the range 8 to 15 mg/L (Aminimanizani and Winter, 2004). Explore the problem as a Linear Plot - Interactive graph
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