Acyclovir (Page 2 of 4)

12.3 Pharmacokinetics

A clinical pharmacology study was performed with Acyclovir Cream in adult volunteers to evaluate the percutaneous absorption of acyclovir. In this study, which included 6 male volunteers, the cream was applied to an area of 710 cm2 on the backs of the volunteers 5 times daily at intervals of 2 hours for a total of 4 days. The weight of cream applied and urinary excretion of acyclovir were measured daily. Plasma concentration of acyclovir was assayed 1 hour after the final application. The average daily urinary excretion of acyclovir was approximately 0.04% of the daily applied dose. Plasma acyclovir concentrations were below the limit of detection (0.01 μM) in 5 subjects and barely detectable (0.014 μM) in 1 subject. Systemic absorption of acyclovir from Acyclovir Cream is minimal in adults.

The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients <18 years of age.

12.4 Microbiology

Mechanism of Action: Acyclovir is a synthetic purine deoxynucleoside analogue with cell culture and in vivo inhibitory activity against HSV types 1 (HSV-1) and 2 (HSV-2) DNA polymerases. It inhibits HSV-1 and HSV-2 replication in cell culture and in vivo.

The inhibitory activity of acyclovir is selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV. This viral enzyme converts acyclovir into acyclovir monophosphate, a deoxynucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This inhibition is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.

Antiviral Activity

The quantitative relationship between the susceptibility of herpes viruses to antivirals in cell culture and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50 value), vary greatly depending upon a number of factors. Using plaque-reduction assays on Vero cells, the EC50 values of acyclovir against herpes simplex virus isolates range from 0.09 to 59.9 μM (0.02 to 13.5 μg/mL) for HSV-1 and from 0.04 to 44.0 μM (0.01 to 9.9 μg/mL) for HSV-2.

Resistance

In Cell Culture
Acyclovir-resistant HSV-1 and HSV-2 strains were isolated in cell culture. Acyclovir-resistant HSV resulted from mutations in the viral thymidine kinase (TK; pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 1).

Table 1: Summary of Acyclovir (ACV) Resistance-associated Amino Acid Substitutions in Cell Culture

HSV-1

TK

P5A, H7Q, L50V, G56V, G59A, G61A, K62N, T63A, E83K, P84S, D116N, P131S, R163H, A167V, P173L, Q185R, R216S, R220H, T245M, R281stop, T287M, M322K

HSV-2

TK

L69P, C172R, T288M

HSV-1

POL

D368A, Y557S, E597D, V621S, L702H, N815S, V817M, G841C

HSV-2

POL

In HSV-Infected Patients

Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their α-herpesvirus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 2). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Table 2: Summary of ACV Resistance-associated Amino Acid Substitutions Observed in Treated Patients

HSV-1

TK

G6C, R32H, R41H, R51W, Y53C/D/H, Y53stop,

D55N, G56D/S, P57H, H58/N/R/Y, G59R,

G61A, K62N, T63I, Q67stop, S74stop, Y80N,

E83K, P84L, Y87H, W88R, R89Q/W, E95stop,

T103P, Q104H, Q104stop, H105P, D116N,

M121L/R, S123R, Q125H, M128L, G129D,

I143V, A156V, D162A/H/N, R163G/H, L170P,

Y172C, P173L, A174P, A175V, R176Q/W,

R176stop, L178R, S181N, V187M, A189V,

V192A, G200C/D/S, T201P, V204G, A207P,

L208F/H, R216C/H, R220C/H, R221H,

R222C/H, L227F, T245M/P, L249P, Q250Stop,

C251G, R256W, E257K, Q261R, T287M,

L288Stop, L291P/R, L297S, L315S, L327R,

C336Y, Q342Stop, T354P, L364P, A365T

HSV-2

TK

R34C, G39E, R51W, Y53N, G59P, G61W,

S66P, A72S, D78N, P85S, A94V, N100H,

I101S, Q105P, T131P, D137stop, F140L,

L158P, S169P, R177W, S182N, M183I,

V192M, G201D, R217H, R221C/H,

Q222stop, R223H, Y239stop, R271V,

P272S, D273R, T287M, C337Y

HSV-1

POL

K532T, Q570R, L583V, A605V, A657T, D672N,

V715G, A719T/V, S724N, F733C, E771Q,

S775N, L778M, E798K, V813M, N815S,

G841S, I890M, G901V, V958L H1228D

HSV-2

POL

E250Q, D307N, K533E, A606V, C625R,

R628C, E678G, A724V, S725G, S729N, I731F,

Q732R, M789K/T, V818A, N820S, Y823C,

Q829R, T843A, M910T, D912N/V, A915V,

F923L, T934A, R964H

Note: Additional substitutions to acyclovir resistance may exist.

Cross-resistance

Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) [Table 3].

Table 3: Summary of Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS

Cross-resistant toPCV/FCV

HSV-1 TK

G6C, R32H, R51W, Y53C/H, H58N, G61A, S74Stop, E83K, P84L, T103P, Q104Stop, D116N, M121R, I143V, R163H, L170P, Y172C, A174P, R176Q/W, Q185R, A189V, G200D, L208H, R216C, R220H, R222C/H, T245M, Q250Stop, R256W, R281Stop, T287M, L315S, M322K, C336Y

Cross-resistant to PCV/FCV

HSV-1 POL

A657T, D672N, V715G, A719V, S724N, E798K, N815S, G841S

Cross-resistant to PCV/FCV

HSV-2 TK

G39E, R51W, Y53N, R177W, R221H, T288M

Cross-resistantto PCV/FCV

HSV-2 POL

K533E, A606V, C625R, R628C, S729N, Q732R, M789K/T, V818A,N820S, F923L, T934A

Cross-resistant to FOS

HSV-1 POL

D368A, A605V, D672N, L702H, V715G, A719T/V, S724N, L778M, E798K, V813M, N815S, V817M, G841C/S, I890M

Cross-resistant to FOS

HSV-2 POL

K533E, A606V, C625R, R628C, A724V, S725G, S729N, I731F, Q732R, M789K/T, V818A, Y823C, D912V, F923L, T934A, R964H

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