ABSTRACT
OBJECTIVES: We developed a population model that describes the ocular penetration and pharmacokinetics of penciclovir in human aqueous humour and plasma after oral administration of famciclovir. METHODS: Fifty-three patients undergoing cataract surgery received a single oral dose of 500 mg of famciclovir prior to surgery. Concentrations of penciclovir in both plasma and aqueous humour were measured by HPLC with fluorescence detection. Concentrations in plasma and aqueous humour were fitted using a two-compartment model (NONMEM software). Inter-individual and intra-individual variabilities were quantified and the influence of demographics and physiopathological and environmental variables on penciclovir pharmacokinetics was explored. RESULTS: Drug concentrations were fitted using a two-compartment, open model with first-order transfer rates between plasma and aqueous humour compartments. Among tested covariates, creatinine clearance, co-intake of angiotensin-converting enzyme inhibitors and body weight significantly influenced penciclovir pharmacokinetics. Plasma clearance was 22.8±9.1 L/h and clearance from the aqueous humour was 8.2×10(-5) L/h. AUCs were 25.4±10.2 and 6.6±1.8 µg·h/mL in plasma and aqueous humour, respectively, yielding a penetration ratio of 0.28±0.06. Simulated concentrations in the aqueous humour after administration of 500 mg of famciclovir three times daily were in the range of values required for 50% growth inhibition of non-resistant strains of the herpes zoster virus family. CONCLUSIONS: Plasma and aqueous penciclovir concentrations showed significant variability that could only be partially explained by renal function, body weight and comedication. Concentrations in the aqueous humour were much lower than in plasma, suggesting that factors in the blood-aqueous humour barrier might prevent its ocular penetration or that redistribution occurs in other ocular compartments.
Subject(s)
2-Aminopurine/analogs & derivatives , Acyclovir/analogs & derivatives , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Aqueous Humor/chemistry , 2-Aminopurine/administration & dosage , Acyclovir/pharmacokinetics , Administration, Oral , Adult , Aged , Aged, 80 and over , Famciclovir , Female , Guanine , Humans , Male , Middle Aged , Models, Statistical , Plasma/chemistryABSTRACT
Prescribing a medication for a condition not described in the label approved by national regulatory bodies (in Switzerland, Swissmedic) is called "off-label" prescribing. Unlicensed drug use is common in all fields of medicine and may be encountered in therapeutic guidelines. The term does not imply improper nor illegal use, and may provide the only available treatment for "orphan" conditions, or for certain populations (children, pregnant women, very old patients). Off-label drug use should be based on sound scientific evidence of efficacy and safety. In Switzerland, patients need to be informed that health insurance coverage is not guaranteed with off-label use. The prescribing physician bears the responsibility of off-label use with the possibility of unanticipated risks, and should therefore be prepared for possible malpractice suits.