Therapeutic effects, interindividual variations

The serum concentrations of "classical neuroleptics and their metabolites vary considerably in patients, even when the dose of drug administered has been standardized. Such interindividual variation may account for the differences in the therapeutic and side effects. High interindividual variations in the steady-state plasma levels have been reported for pimozide, fluphenazine, flupenthixol and haloperidol, some of these differences being attributed to differences in absorption and metabolism between patients. 

Individual genetically determined variations in transporter function may contribute to interindividual differences in therapeutic and/or adverse effects of drugs. Several studies have shown that variations in transporter gene sequences do occur. However, the clinical significance of these variations generally is not yet well documented. For example, as discussed in Chapter 4, the intestinal hPEPT-1 transporter plays a role in absorption of peptide-like cephalosporin antibiotics and other drugs. Interindividual variations in hPEPT-1 may account for the large interindividual variations in bioavailability that have been observed (129). 

The steady-state concentrations of antipsychotic drugs after multiple dosing have been measured to establish a relationship between plasma concentrations and clinical efficacy or to monitor adverse effects (360-363). The majority of drugs in the class seem to exhibit linear pharmacokinetics, despite the wide interindividual variations in pharmacokinetic properties observed for specific agents. Linear pharmacokinetics allows the dosage to be readily adjusted if the steady-state plasma concentration is in the sub-therapeutic or toxic range. 

Interindividual differences in drug delivery to its site(s) of action can profoundly influence therapeutic effectiveness and adverse effects. Some of the determinants of interindividual variation are... 

Studies of oropharyngeal deposition in healthy subjects (30-32), as well as in patients with asthma (33) have shown wide interindividual variations. For instance, deposition in the oropharynx of inhaled 3.6-pm test particles varied between 10 and 70% in asthmatics. This implies that the dose of a therapeutic aerosol in the lungs is difficult to predict and is sometimes suboptimal. Furthermore, adverse effects of inhaled corticosteroids, such as oral candidiasis (34), dysphonia (35), and osteoporosis (36), may arise locally and systematically. It is evidently important to reduce a high oropharyngeal deposition. 

The evaluation of a dose-effect relationship within a group of human subjects is compounded by interindividual differences in sensitivity. To account for the biological variation, measurements have to be carried out on a representative sample and the results averaged. Thus, recommended therapeutic doses will be appropriate for the majority of patients, but not necessarily for each individual. 

Theophylline is not only characterized by a narrow therapeutic index and distinct relationships between serum concentration and therapeutic and toxic effects, but also by a high interindividual pharmacokinetic variabihty. This variability is predominantly based on a high patient-to-patient variability in the metabolic clearance of theophylline that is confounded by numerous additional physiological, pathophysiological, and enviromnental factors. Intravenous theophylhne (given as aminophyl-line), for example, has been shown to result in considerable variations in serum concentrations among patients despite the same dose, and theophylline dose requirements to maintain serum concentration in the range of 10 to 20 lig/ml varied from 400 to 3200 mg/day. ... 

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