title: Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model.
abstract: OBJECTIVE
  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.
authors.affiliation: Clinical Pharmacology and Toxicology Service, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Fanny
authors.initials: F
authors.lastname: Schenkel
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.forename: Edoardo
authors.initials: E
authors.lastname: Baglivo
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Kondo-Oestreicher
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Marianne
authors.initials: M
authors.lastname: Gex-Fabry
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
mesh_terms: D015075:2-Aminopurine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000212:Acyclovir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000737:chemistry*; D000077595:Famciclovir; D005260:Female; D006147:Guanine; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010949:Plasma / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; C053539:penciclovir; D015075:2-Aminopurine; D006147:Guanine; D000077595:Famciclovir; D000212:Acyclovir
keywords: antiviral therapy; ophthalmic viral infections; pharmacokinetic modelling