Pharmacokinetics of acyclovir in immunocompromized children with leukopenia and mucositis after chemotherapy: can intravenous acyclovir be substituted by oral valacyclovir?
BACKGROUND
The efficacy of oral acyclovir, a purine nucleoside analogue with activity against human herpes viruses, is limited as a result of its low bioavailability. Valacyclovir, the L-valyl ester of acyclovir, has been developed as a pro-drug to improve the bioavailability. The aim of the present study was to compare the pharmacokinetics of acyclovir after intravenous administration and after oral administration of valacyclovir.


METHODS
The pharmacokinetics of acyclovir were studied in 18 children aged 1.4-18.1 years (median: 6.9 years; 9 females) after intravenous infusion (1 hr; median dose: 10.5 mg/kg). In 10 of the children the pharmacokinetics of acyclovir were also studied after oral administration of valacyclovir (median dose: 34.1 mg/kg). Quantification of acyclovir in serum was performed by reversed-phase liquid chromatography with fluorometric detection. The pharmacokinetic analysis was performed by pharmacokinetic modelling.


RESULTS
The serum concentration versus time curves of acyclovir were described by the two compartment model after intravenous administration and by the one compartment model with a zero- or first-order absorption phase after oral administration of valacyclovir. The bioavailability of acyclovir after oral administration of valacyclovir was 45% (median value; 95% CI: 37-55%).


CONCLUSIONS
It is possible to substitute intravenous acyclovir therapy by oral valacyclovir therapy in children with leukopenia and mucositis after chemotherapy. This finding can at present not be fully implemented in clinical practice, since a commercial pharmaceutical formulation of valacyclovir aimed for children not able to swallow intact tablets is lacking. Crushed valacyclovir tablets have a very unpleasant taste, but can be administered to children through nasogastric tubes.
Eksborg
Staffan
S
Karolinska Pharmacy, Karolinska Hospital, SE-171 76 Stockholm, Sweden. stygge.staffan@swipnet.se
Pal
Niklas
N
Kalin
Mats
M
Palm
Carina
C
Söderhäll
Stefan
S
D000212:Acyclovir / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D005260:Female; D006561:Herpes Simplex / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced*; D008297:Male; D009061:Mouth Mucosa; D011355:Prodrugs / Q000008:administration & dosage*; D013280:Stomatitis / Q000139:chemically induced*; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage* / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011355:Prodrugs; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir