ACTIVITY OF (S)-1-(3-HYDROXY-2-PHOSPHONYLMETHOXYPROPYL) CYTOSINE AGAINST HUMAN CYTOMEGALOVIRUS WHEN ADMINISTERED AS SINGLE-BOLUS DOSE AND CONTINUOUS-INFUSION IN IN-VITRO CELL-CULTURE PERFUSION SYSTEM

HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine] is a pote nt inhibitor of human cytomegalovirus (HCMV) replication as determined by conventional tissue culture methods in which the drug concentratio n remains constant over time. Previous studies have shown HPMPC to hav e a long intracellular half life. Despite its relatively short extrace llular half-life, HPMPC might provide significant anti-HCMV activity l ong after the elimination of the drug by first order kinetics. We addr essed this hypothesis by measuring the activity of HPMPC in a novel ce ll culture perfusion system. This system allows us to compare the acti vity of HPMPC when given as a continuous infusion with its activity wh en given as a single-bolus dose followed by elimination that simulates the drug's in vivo pharmacokinetics. We show that continuous infusion s maintaining maximum concentrations (C(max)s) of 0.05, 0.10, 0.31, an d 1.0 mu g/ml and achieving areas under the drug concentration-time cu rves (AUCs) of 8.4, 17, 50, and 162 mu g.h/ml, respectively, result in 27, 56, 63, and 88% inhibition of viral DNA accumulation, respectivel y, compared with an untreated control. Single-bolus doses achieving C( max)s of 0.10, 1.25, 3.0, and 7.7 mu g/ml with an elimination half-lif e of 20 h achieved AUCs of 2.4, 32, 78, and 138 mu g.h/ml and resulted in 0, 48, 69, and 87% inhibition of HCMV DNA accumulation. Single bol us doses achieving C(max)s of 3.9 and 12 mu g/ml with an elimination h alf-life of 6.5 h achieved AUCs of 34 and 105 mu g.h/ml, respectively, resulting in 15 and 76% inhibition of viral DNA accumulation. Compari son of C-max-versus-effect curves for these three regimens suggests th at maximum concentration is not the only important pharmacokinetic det erminant of HPMPC's antiviral activity. Similar comparisons of AUC-ver sus-effect curves for continuous and bolus dosing suggest that the AUC is an important determinant of antiviral activity for AUCs greater th an 100 mu g.h/ml. We conclude that single-bolus doses of HPMPC potentl y inhibit HCMV DNA accumulation but that this activity is more heavily influenced by the AUC than the C-max at the upper end of the AUC rang e tested. At lower AUCs, some other parameter may be the primary deter minant of antiviral activity. Our cell culture perfusion system provid es a novel, efficient, and convenient method for addressing questions relating the effects of constantly changing drug concentrations to ant iviral effects.