Latin substance name Valaciclovir
L-valine 2 – [(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester (as hydrochloride)
Pharmacological group of substance Valaciclovir
Nosological classification (ICD-10)
Characteristics of the substance Valaciclovir
Valacyclovir is the hydrochloride salt of acyclovir L-valyl ester. Valaciclovir hydrochloride – white or almost white powder; maximum solubility in water (at 25 ° C) – 174 mg / ml; molecular weight 360.80.
Valacyclovir is a prodrug in the body that is rapidly and almost completely converted to acyclovir, which after phosphorylation acquires specific activity. Acyclovir is a structural analogue of purine nucleosides (normal DNA components), interacts with viral DNA polymerase and blocks the reproduction of viruses. Selective antiherpetic activity is due to the affinity for thymidine kinase Herpes simplex, Varicella zoster and Epstein-Barr virus. Under the action of thymidine kinase, viruses are transformed into acyclovir monophosphate, with the participation of guanylate kinase of human cells, into acyclovird diphosphate and then into the active form acyclovir triphosphate. Triphosphate blocks viral DNA replication by competitively inhibiting viral DNA polymerase and inhibiting DNA strand elongation. In vitro acyclovir is active against Herpes simplex Type 1 and Type 2 viruses, Varicella zoster (less active than Herpes simplex, due to more efficient phosphorylation of the corresponding thymidine kinase), Epstein-Barr virus, CMV and human herpes virus type 6.
The resistance of the Herpes simplex and Varicella zoster strains develops due to a phenotypic deficiency of viral thymidine kinase, or due to hidden changes in thymidine kinase or DNA polymerase; resistance occurs in exceptional cases in patients with normal immunological status and much more often against the background of pronounced immunodeficiency (with HIV infection, in patients receiving chemotherapy for malignant neoplasms, etc.).
After oral administration, valaciclovir is rapidly absorbed from the gastrointestinal tract and as a result of metabolism during the “first pass” through the intestine and / or liver, due to enzymatic hydrolysis, it is rapidly and almost completely (99%) converted into acyclovir and L-valine.
The pharmacokinetics of valaciclovir and acyclovir after oral administration have been studied in 14 studies in healthy adult volunteers (n = 283).
When taking valaciclovir hydrochloride in a dose of 1000 mg, the absolute bioavailability of acyclovir is (54.5 ± 9.1)% and does not depend on food intake. Pharmacokinetic parameters after administration of various doses of valaciclovir hydrochloride are not proportional to dose. So, after a single dose of valaciclovir hydrochloride in doses of 100, 250, 500, 750 and 1000 mg of Cmax, acyclovir reaches 0.83; 2.15; 3.28; 4.17 and 5.65 µg / ml, AUC – 2.28; 5.76; 11.59; 14.11 and 19.52 h · μg / ml, respectively. After repeated administration of valaciclovir hydrochloride in doses of 250, 500 and 1000 mg 4 times a day for 11 days, Cmax – 2.11; 3.69 and 4.96 µg / ml and AUC – 5.66; 9.88 and 15.70 h · μg / ml, respectively. Tmax is 1.6–2.1 h. Concentration in plasma of unchanged valacyclovir is low, Cmax is below 0.5 µg / ml at all doses studied, after 3 h valaciclovir is no longer detected in plasma; binding of valacyclovir to plasma proteins – 13.5–17.9%. Acyclovir is biotransformed by the action of alcohol and aldehyde dehydrogenase and, to a lesser extent, aldehyde oxidase into inactive metabolites. The metabolism of valaciclovir / acyclovir is not associated with cytochrome P450 enzymes.
T1 / 2 of valaciclovir – less than 30 minutes, T1 / 2 of acyclovir after taking valaciclovir hydrochloride is 2.5–3.3 h (in healthy volunteers with normal renal function), in elderly patients (65 years – 83 years) – 3.3 –3.7 h, increased in patients with end-stage renal disease. Valacyclovir is excreted in the urine (45.6%) and in feces (47.12%) within 96 hours. The renal clearance is about 255 ml / min. Of the total amount of valaciclovir excreted by the kidneys, more than 80–89% is eliminated as acyclovir. Less than 1% of valaciclovir is displayed unchanged. After repeated use of valaciclovir in patients with normal renal function, acyclovir does not accumulate.
The dependence of pharmacokinetic parameters on some factors
Liver disease. In patients with diseases of the liver, moderate (cirrhosis, proven by biopsy) or severe (biopsy-proven cirrhosis with / without ascites) rate, but not the conversion of valacyclovir to acyclovir, decreases; T1 / 2 acyclovir does not change.
HIV-infected patients. In 9 patients with HIV (CD4 cell count 3), when taking valaciclovir hydrochloride at a dose of 1000 mg 4 times a day for 30 days, the pharmacokinetic indicators of valacyclovir and acyclovir did not differ from those observed in healthy volunteers.
Teratogenicity Valacyclovir did not exert a teratogenic effect in rats and rabbits when administered in doses of 400 mg / kg during organogenesis (plasma concentrations exceeding those in humans 10 and 7 times, respectively).
Fertility Valacyclovir did not cause fertility disorders in males and females of rats treated with a dose of 200 mg / kg / day (the concentration in the blood was 6 times higher than in humans).
Clinical trials of valaciclovir in children
65 children from 12 to 18 years old took a tablet form of valacyclovir inside for 1-2 days about herpes. The frequency, nature and intensity of undesirable side reactions (including deviations of laboratory parameters) were similar to those in the group of adult patients.
A group of adolescent patients who received valaciclovir at a dose of 1-2 g 2 times a day for 1 day (n = 65) and a placebo group (n = 30) had a headache (17%, 3%), nausea ( 8%, 0%).
Use of the substance Valaciclovir
Shingles; infections of the skin and mucous membranes caused by the herpes simplex virus (in
Restrictions on the use of
Renal impairment, clinically significant forms of HIV infection, children under 12 years of age (safety and efficacy have not been determined).
Use during pregnancy and lactation
Pregnancy. It is possible if the expected effect of therapy exceeds the potential risk to the fetus (adequate and strictly controlled studies of the safety of use in pregnant women have not been carried out).
Data on the outcome of pregnancy in women who took systemic acyclovir in the first trimester of pregnancy (acyclovir is an active metabolite of valacyclovir) did not show an increase in the number of congenital malformations in children compared to the general population. Since the observation included a small number of women, reliable and definite conclusions about the safety of valaciclovir during pregnancy cannot be made.
Category of action on the fetus by the FDA – B.
Lactation. Acyclovir, the main metabolite of valaciclovir, is excreted in breast milk. After the oral administration of valaciclovir at a dose of 500 mg Cmax of acyclovir in breast milk, it was 0.5–2.3 times (on average 1.4 times) higher than the corresponding concentrations in the mother’s blood. The ratio of AUC of acyclovir in breast milk to AUC of acyclovir in the mother’s plasma was 1.4–2.6 (average 2.2). The average concentration of acyclovir in breast milk is 2.24 µg / ml. When prescribing valaciclovir in a nursing mother at a dose of 500 mg, 2 times a day, the child will be exposed to the same effects of acyclovir as when taken orally at a dose of about 0.61 mg / kg / day. Valaciclovir in unchanged form is not detected in the blood and breast milk of the mother or the urine of the child. Valaciclovir should be administered to lactating women with caution, only if necessary.
Additional information on the use of valacyclovir during pregnancy
There have not been sufficient controlled clinical trials for valaciclovir in pregnant women. Based on data from prospective studies on the use of valaciclovir against 749 pregnancies, it can be said that the ratio of the incidence of birth defects in children exposed to valacyclovir during fetal development and in children in the general population is the same. Valaciclovir can be used during pregnancy only when the potential benefit to the mother outweighs the potential risk to the fetus.
Side effects of Valaciclovir
Table 1 presents the side effects often observed in the treatment with valaciclovir (1 g 3 times a day) in immunocompetent patients with shingles during the randomized double-blind clinical trials.
Side effects observed during clinical trials in patients with shingles