12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Antiviral Action
Acyclovir is an antiviral drug [see Microbiology (12.4)].
12.3 Pharmacokinetics
It has not been possible to detect acyclovir concentrations in the blood by existing bioanalytical methods after topical applicationto the eye. Trace quantities are detectable in the urine but are not therapeutically relevant.
12.4 Microbiology
Acyclovir is a synthetic purine nucleoside analogue that is phosphorylated intracellularly by the viral encoded thymidine kinase(TK) of HSV into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate bycellular guanylate kinase and into triphosphate by a number of cellular enzymes. In a biochemical reaction, acyclovirtriphosphate inhibits replication of herpes viral DNA by competing with nucleotides for binding to the viral DNA polymerase andby incorporation into and termination of the growing viral DNA chain. The cellular thymidine kinase of normal, uninfected cellsdoes not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low.
Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpes virus to antivirals and theclinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized.
Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture(EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, on Vero cells, the median EC50 valueof acyclovir against clinical herpes simplex virus isolates (subjects receiving placebo) was 1.3 µM (range: < 0.56 to 3.3 µM).
Drug Resistance: Resistance of HSV to acyclovir can result from qualitative and quantitative changes in the viral TK and/orDNA polymerase. Clinical isolates of HSV with reduced susceptibility to acyclovir have been recovered from immunecompromised patients, especially with advanced HIV infection. While most of the acyclovir resistant mutant isolates thus far from such patients have been found to be TK deficient, other mutant isolates involving the viral TK gene (TK partial and TK altered) orDNA polymerase have been identified. TK negative mutants may cause severe disease in infants and immune compromisedadults.
The possibility of viral resistance to acyclovir should be considered in immunocompromised patients who show poorclinical response during therapy.
13 NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility:
Acyclovir was not shown to be carcinogenic in mouse and rat bioassays at oral doses up to 450mg/kg (approximately 1100 –2200 times the maximum RHOD, on a mg/m2 basis, assuming 100% absorption).
Acyclovir was tested in 16 in vitro and in vivo genetic toxicity assays. Acyclovir was found to be negative in the Ames test,positive in the in vitro mouse lymphoma assay (TK locus), and positive in the in vitro and in vivo assays for chromosomal effects.
In reproduction studies, acyclovir did not impair fertility or reproduction at oral doses up to 450 mg/kg/day in mice (1100 times theRHOD), or at subcutaneous doses of 25 mg/kg/day in rats (125 times the RHOD). At a dose of 50 mg/kg/day in rats and rabbits(250 and 500 times the RHOD, respectively), implantation efficiency was decreased.
14 CLINICAL STUDIES
In five randomized, double mas |
