or viral DNA polymerase than host cell DNA polymerase and therefore selectively interferes with the viral enzyme causing inhibition of viral DNA replication. Aciclovir is also incorporated into viral DNA by viral DNA polymerase, which results in chain termination, as Aciclovir lacks a 3'-hydroxyl group, preventing addition of nucleotides by 3', 5'-linkage.
In several immunocompromised patients a longer or repeated treatment with Aciclovir can lead to a selection of viral strains with reduced sensitivity. As a result, these patients no longer respond to treatment with Aciclovir. Most of the clinical isolates with reduced sensitivity showed a relative lack of virus thymidine kinase. However, strains with changed/different virus thymidine kinase or DNA polymerase were also reported. The in vitro exposition of HSV-isolates can also lead to the development of less sensitive strains. The connection between the in vitro determined sensitivity of HSV-isolates and the clinical response to the treatment with Aciclovir is not clear.
In two large, double blind, randomised clinical studies involving 1,385 subjects treated over 4 days for recurrent herpes labialis, Aciclovir Cream 5% was compared to vehicle cream. In these studies, time from start of treatment to healing was 4.6 days using Aciclovir Cream and 5.0 days using vehicle cream (p<0.001). Duration of pain was 3.0 days after start of treatment in the Aciclovir Cream group and 3.4 days in the vehicle group (p=0.002). Overall, approximately 60% of patients started treatment at an early lesion stage (prodrome or erythema) and 40% at a late stage (papule or blister). The results were similar in both groups of patients.
5.2 Pharmacokinetic properties
Absorption and plasma concentrations
Aciclovir penetrates into the skin. The intracutaneous concentration levels are higher than the minimal inhibitory concentration (MIC) in tissue at steady state.
After topical application of Aciclovir, no Aciclovir plasma concentration could be determined.
As the Aciclovir plasma concentrations following topical application are below the limit of detection, no pharmacokinetic studies are available on topical Aciclovir. Therefore, the following data is based on the data after oral or intravenous administration.
Plasma protein binding is reported to range between 9% and 33% as a function of dose. The volume of distribution at steady state in adults is 50 ± 8.71ν1.73 m2, or 0.7 l/kg.
Two metabolites could be identified in the urine of patients with normal renal function after single dosing with 14C-Aciclovir: 9-carboxymethoxymethylguanine (2%-14% of an administered dose) and 8-hydroxy-9-(2-hydroxyethoxymethyl) guanine (<0.2% of a dose). Subjects with normal renal function eliminate 62%-91% of an Aciclovir dose unchanged and 9%-14% as 9-carboxymethoxymethylguanine via the kidneys.
Aciclovir is predominantly eliminated via the kidneys, preliminary by glomerular filtration and to a lesser extent by tubular secretion.
In vitro and in vivo studies of Aciclovir cream and Aciclovir ointment versus oral Aciclovir were carried out to determine the bioavailability of Aciclovir in human skin. The in vitro studies used human skin biopsies, whilst the bioassays either used human skin grafts on mice or were carried out in the human eye (3 patients).
The following dermal drug concentration gradient emerged for both topical and oral Aciclovir: stratum corn
