S-Carboxymethyl-l-cysteine: a multiple dosing study using pharmacokinetic modelling

S-Carboxymethyl-l-cysteine is a mucolytic agent used as adjunctive therapy in the treatment of respiratory disorders. Various mechanisms of action have been proposed but few studies have attempted to link the required in vitro concentrations with those achieved actually in vivo during clinical therapy. The data from several published studies has been re-analysed by WinNonlin using non-compartmental analysis modelling, Phoenix modelling and Classic PK compartmental modelling for both single (500-1500 mg) and multiple oral administration of the drug. Multiple dose modelling indicated maximum peak concentrations (C-max) ranging from 1.29 to 11.22 mu g/ml and those at steady state (C-ss(av)) from 1.30 to 8.40 mu g/ml. For the standard therapeutic regimen of 3 x 750 mg (2250 mg/day) these values were 1.29-5.22 mu g/ml (C-max) and 1.30-3.50 mu g/ml (C-ss(av)). No accumulation was observed. Hence, only the pharmacodynamic studies reporting significant effects below c.10 mu g/ml were likely to occur in vivo and these were mainly gene-related mechanisms. The majority of events, although demonstrable in vitro, required levels much greater than possible to achieve in the clinical situation. Such unappreciated disregard for in vitro-in vivo 'concentration matching' may lead to erroneous conclusions regarding mechanisms of action for many drugs as well as for S-carboxymethyl-l-cysteine.

Automated summary

S-Carboxymethyl-l-cysteine is a mucolytic agent used in the treatment of respiratory disorders, with multiple dose modeling indicating effective concentrations ranging from 1.30 to 8.40 μg/mL in the clinical setting. Pharmacodynamic studies reporting significant effects below approximately 10 μg/mL may occur in vivo, mainly through gene-related mechanisms. However, most events requiring levels much higher than achievable in clinical situations were only demonstrable in vitro.