ACYCLOVIR — acyclovir sodium
Fresenius Kabi USA, LLC
Acyclovir Sodium Injection is a synthetic nucleoside analog, active against herpes viruses. It is a sterile, aqueous solution for intravenous infusion, containing 50 mg acyclovir per mL in Water for Injection, USP. The concentration is equivalent to 54.9 mg of acyclovir sodium per mL in Water for Injection, USP. The sodium content is approximately 5.1 mg/mL. The pH range of the solution is 10.85 to 11.50. Further dilution of Acyclovir Sodium Injection in an appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION, Administration). The chemical name of acyclovir sodium is 9-[(2-Hydroxyethoxy)methyl] guanine, and has the following structural formula:
Acyclovir sodium is a white, crystalline powder with the molecular formula C8 H10 N5 NaO3 and a molecular weight of 247.19. The maximum solubility in water at 25°C exceeds 100 mg/mL. At physiologic pH, acyclovir sodium exists as the unionized form with a molecular weight of 225 and a maximum solubility in water at 37°C of 2.5 mg/mL. The pka’s of acyclovir are 2.27 and 9.25.
Mechanism of Antiviral Action
Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2) and varicella-zoster virus (VZV).
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro , acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in three 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. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals 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 (IC50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL.
Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from such patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.
The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every 8 hours. Proportionality between dose and plasma levels is seen after single doses or at steady-state after multiple dosing. Average steady-state peak and trough concentrations from 1-hour infusions administered every 8 hours are given in Table 1.
|Dosage Regimen||CSS max||CSS trough|
|5 mg/kg q 8 h (n=8)||9.8 mcg/mLrange: 5.5 to 13.8||0.7 mcg/mLrange: 0.2 to 1|
|10 mg/kg q 8 h (n=7)||22.9 mcg/mLrange: 14.1 to 44.1||1.9 mcg/mLrange: 0.5 to 2.9|
Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein binding is relatively low (9% to 33%) and drug interactions involving binding site displacement are not anticipated.
Renal excretion of unchanged drug is the major route of acyclovir elimination accounting for 62% to 91% of the dose. The only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function.
The half-life and total body clearance of acyclovir are dependent on renal function as shown in Table 2.
|Creatinine Clearance (mL/min/1.73 m2)||Total Body Clearance|
|Half-Life (hr)||(mL/min/1.73 m2)||(mL/min/kg)|
|50 to 80||3||248||3.9|
|15 to 50||3.5||190||3.4|
Adults with Impaired Renal Function
Acyclovir was administered at a dose of 2.5 mg/kg to 6 adult patients with severe renal failure. The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.
Consult DOSAGE AND ADMINISTRATION section for recommended adjustments in dosing based upon creatinine clearance.
Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours (Table 3). Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively (Table 1). Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours (Table 3).
|Parameter||Aged from Birth to 3 Months (n=12)||Aged 3 Months to 12 Years (n=16)|
|CL (mL/min/kg)||4.46 ± 1.61||8.44 ± 2.92|
|VDSS (L/kg)||1.08 ± 0.35||1.01 ± 0.28|
|Elimination half-life (hours)||3.8 ± 1.19||2.36 ± 0.97|
Acyclovir pharmacokinetic samples were collected in full-term and pre-term neonates with normal renal function who received varying dosing regimens of acyclovir for the treatment of suspected neonatal HSV infection. Model-predicted pharmacokinetic parameters stratified by post-menstrual age (PMA) are summarized in Table 4.
a Administered over 1 hour.
|Post-MenstrualAge (PMA)||n||IV Dosea||Parameter (Median [Range])|
|Cminss (mg/L)||Cmaxss (mg/L)||CL(L/h/kg)||V(L/kg)|
|<30 Weeks||13||500 mg/m2 every 8 hor10 or 20 mg/kg every 12 h||3.92(2.38 — 39.3)||10.3(4.59 — 110)||0.21(0.10 — 0.31)||2.88(0.65 — 5.30)|
|30 to <36 Weeks||9||500 mg/m2 every 8 hor10 or 20 mg/kg every 12 hor20 mg/kg every 8 h||5.10(2.54 — 9.62)||8.83(5.44 — 29.8)||0.45(0.30 — 0.81)||4.49(1.87 — 10.85)|
|36 to 41 Weeks||6||500 mg/m2 every 8 h||2.90(2.19 — 7.46)||12.4(10.8 — 86.1)||0.59(0.13 — 0.77)||2.55(0.29 — 4.09)|
|Overall||28||–||4.15(2.19 — 39.3)||11.1(4.59 — 110)||0.28(0.10 — 0.81)||3.34(0.29 — 10.9)|
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