Paulo de Miranda

Pharmacokinetics of the acyclovir pro‐drug valaciclovir after escalating single‐and multiple‐dose administration to normal volunteers

The pharmacokinetics and safety of the L‐valyl ester pro‐drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo‐controlled trials in normal volunteers. These included a single‐dose study with doses from 100 to 1000 mg (single cohort) and a multiple‐dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (~ threefold to fivefold) compared with that historically observed with high‐dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration‐time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

Activity of 9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine in the Treatment of Cytomegalovirus Pneumonia

Ten marrow transplant recipients with biopsy-proven cytomegalovirus pneumonia were treated with the acyclic nucleoside analog 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (BW B759U). Viruria and viremia ceased after 4 days of treatment in all patients with cultures initially positive from these sites. Cytomegalovirus was eliminated from respiratory secretions after a median of 8 days. Despite this antiviral effect, only one patient survived the pneumonia. Quantitative cultures of lung tissue before and after treatment confirmed that therapy with BW B759U was associated with substantial antiviral activity, with a mean decrease in viral titers of more than 99.99% after treatment. Neutropenia developed in three patients when mean peak and trough plasma levels exceeded 50 and 10 mu mol/L, respectively, but no other toxicity was seen. BW B759U is the first antiviral agent showing consistent activity against cytomegalovirus in vivo, and it should be evaluated in the earlier management of cytomegalovirus infections after marrow transplantation and in serious cytomegalovirus infections in other immunocompromised patients.

Overview of acyclovir pharmacokinetic disposition in adults and children.

The metabolic disposition and pharmacokinetics of acyclovir have been studied as part of the clinical evaluation of the drug in humans. Data from 10 studies have been summarized and, when appropriate, pooled across studies for further analysis. The principal findings are as follows: Renal excretion is the major route of elimination of acyclovir and is dependent, in part, on active tubular secretion. Total body clearance (Cltot) and half-life are dependent on renal function as evaluated by estimated creatinine clearance (Clcr). Cltot is markedly reduced in the anuric patient. Plasma protein binding is low and drug interactions involving binding displacement are not anticipated. Acyclovir levels in cerebrospinal fluid are approximately 50 percent of corresponding plasma levels. Dose-independent pharmacokinetics is observed in the range of 0.5 to 15 mg/kg. Proportionality between dose and plasma levels is seen after single doses or at steady state after multiple dosing. Similar plasma levels are achieved in adults and pediatric patients (greater than 1 year) when equivalent doses are given based on body surface area. Intrasubject variability of acyclovir disposition is low. Much but not all intersubject variability in Cltot can be explained by differences in renal function. Dosage adjustment for various stages of renal impairment are proposed based on the observed relationship between Cltot and Clcr.

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS‐related complex

The anti–human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5′‐glucuronide (GAZT) and is cleared rapidly, resulting in a short half‐life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is adminstered orally to patients with acquired immunodeficiency syndrome (AIDS) or AIDS‐related complex (ARC). The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean AUC, a corresponding decline in the apparent total clearance, and a prolongation in the mean half‐life. Similar alterations were observed in GAZT disposition. There was a marked reduction in the urinary excretion ratio of GAZT to zidovudine and a decline in the renal clearance of GAZT after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of GAZT.

Nonclinical toxicology studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats.

Zidovudine (ZDV), an antiviral drug active in the treatment of acquired immunodeficiency syndrome (recommended human dose, 100 mg every 4 hr while awake), was evaluated for mutagenic and carcinogenic potential in a battery of short-term in vitro and in vivo assays and in lifetime studies in mice and rats. In L5178Y mouse lymphoma cells (tk+/- locus), a weak positive result was obtained only at the highest concentrations tested (4000 to 5000 micrograms/ml) in the absence of metabolic activation. In the presence of metabolic activation, the drug was weakly mutagenic at concentrations of 1000 micrograms/ml and higher. Following 24 hr treatment in the absence of metabolic activation, ZDV was moderately mutagenic at concentrations up to 600 micrograms/ml; dose-related structural chromosomal alterations were seen at concentrations of 3 micrograms/ml and higher in cultured human lymphocytes. Such effects were not noted at the two lowest concentrations tested, 0.3 and 1 microgram/ml, and BALB/c-3T3 cells were transformed at concentrations of 0.5 microgram/ml and higher. No effects were seen in the Ames Salmonella plate incorporation and preincubation modification assays (possibly due to bacteriocidal activity of ZDV at low concentrations) at concentrations ranging from 0.01 to 10 micrograms/plate or in a single-dose intravenous bone marrow cytogenetic assay in CD rats. In multidose micronucleus studies, increases in micronucleated erythrocytes were seen in mice at doses of 100 to 1000 mg/kg/day. Similar results were seen in rats and mice after 4 or 7 days of dosing at 500 mg/kg/day. In carcinogenicity bioassays, adjusted doses of 20, 30, or 40 mg/kg/day and 80, 220, and 300 mg/kg/day were given to CD-1 mice and CD rats, respectively, for up to 22 months in mice and 24 months in rats. ZDV caused a macrocytic, normochromic anemia in both species. No evidence of carcinogenicity was seen in male mice or rats. In female mice, five malignant and two benign vaginal epithelial neoplasms occurred in animals given 40 mg/kg/day. A single benign vaginal epithelial tumor was seen in a mouse given 30 mg/kg/day. In rats, two malignant vaginal epithelial neoplasms were seen in animals given 300 mg/kg/day. In a 7-day study in mice, ZDV was shown to be devoid of estrogenic activity. In an oral pharmacokinetics study, the AUC was 17 and 140 micrograms/ml.hr in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. In contrast, the average steady-state concentration in humans at the recommended daily dose is 0.62 microgram/ml. Twenty-four hour urine concentrations were 1245 and 4417 micrograms/ml in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. These values were approximately 26- and 136-fold higher than the human urine concentration at the recommended daily dose. In a one- to three-day study with intravenously administered sodium fluoroscein in rats and mice, retrograde flow of urine into the vagina was demonstrated. In a subsequent lifetime carcinogenicity bioassay in mice in which ZDV was given intravaginally at concentrations of 5 or 20 mg ZDV/ml in saline, 13 vaginal squamous cell carcinomas were seen at the highest concentration tested. It was concluded that the vaginal tumors seen in the oral carcinogenicity studies were the result of chronic local exposure of the vaginal epithelium to high urine concentrations of ZDV.

Species differences in the disposition of acyclovir

The disposition of acyclovir was investigated in several species. The drug was well distributed into all the tissues, including the brain, in mice and rats. Binding of acyclovir to plasma proteins was 36 percent or lower. After intravenous bolus dosing (20 mg/kg) in dogs, the plasma acyclovir concentration-time profile, determined by radioimmunoassay, showed a biphasic decline with a half-life in the elimination phase of 2.3 +/- 0.1 hours. The volume of distribution (Vd beta) of 1.2 +/- 0.2 liters/kg indicated distribution of drug into the tissues. Marked species differences were observed in the gastrointestinal absorption and biotransformation of acyclovir. Oral dosing produced better absorption in dogs and mice than in rats and rhesus monkeys. More than 95 percent of the radioactivity in the urine derived from a 14C-acyclovir parenteral dose was recovered as the unchanged drug in mice, rats, and dogs. Minor urinary metabolites were characterized by high-performance liquid chromatography as 9-carboxymethoxymethylguanine (CMMG) and 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. In other species--guinea pig, rabbit, and rhesus monkey--up to 40 percent of the radioactivity in the urine consisted of these metabolites.

Preclinical toxicology studies with acyclovir: teratologic, reproductive and neonatal tests.

Five studies were done to define the potential of Acyclovir (ACV), a new nucleoside analog for antiviral chemotherapy, to produce adverse effects on reproduction and development in laboratory animals. ACV produced no adverse effects when given by gavage to F0 generation mice at 50, 150 and 450 mg/kg/day in a two generation reproduction/fertility study. Some mice were evaluated for teratologic effects and others for postnatal development, including behavior, with negative results. ACV was not embryotoxic and did not increase the incidence of fetal malformations when given by subcutaneous injection to pregnant rats and rabbits at dose levels of 12, 25 and 50 mg/kg/day during the periods of major organogenesis. A comparative LD50 study revealed that 3-day-old rats were not more sensitive to acute toxic effects of ACV than more mature rats. Finally, in a comprehensive multidose toxicity study ACV was given subcutaneously to neonatal rats at 5, 20 and 80 mg/kg/day for 19 consecutive days. There was minimal effect on body weight gain in neonates treated at 20 mg/kg/day and a significant decrease in body weight gain at 80 mg/kg/day. Minimal renal lesions occurred at 80 mg/kg/day but no other signs of adverse effects on developing organ systems were observed. Except for decreased body weight gain in neonatal rats treated at 80 mg/kg/day, ACV did not produce adverse effects on mammalian development when tested in a variety of preclinical toxicology studies.

Preclinical toxicology studies with acyclovir: Acute and subchronic tests

Acyclovir (ACV), a new antiherpes drug, was evaluated for toxicity in a series of acute and subchronic toxicity tests. Oral LD50 values were greater than 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kg in male Long Evans rats. When ACV was given iv, the LD50 was 405 mg/kg for male mice and greater than 600 mg/kg for male rats. Additionally, LD50 values for male rats treated sc were 1070, 790, 678, and 650 mg/kg in rats that were respectively, 3, 10, 28 and 71 days old indicating that very young rats were not more sensitive to acute toxic effects of ACV. There were no signs of toxicosis in CD-1 mice given ACV by gavage at dose levels of 50, 150 and 450 mg/kg/day for 1 month. Obstructive nephropathy occurred in rats given 20, 40 and 80 mg/kg/day once each day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/day were no effect dose levels. Renal damage caused by precipitation of drug crystals in renal tubules and collecting ducts in rats given ACV by rapid iv injection was readily reversible within 2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and 100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogs given 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of 8 dogs given 50 mg/kg b.i.d. died after 21 to 31 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure

The pharmacokinetic disposition of acyclovir was studied in six patients with chronic renal failure (CRF) and anuria. At the end of a one-hour intravenous infusion (2.5 mg/kg), the mean peak acyclovir plasma level (+/- SD), determined by radioimmunoassay, was 37.5 +/- 24.2 microM (8.4 +/- 5.4 microgram/ml), twice the level found at this dose in patients with normal renal function (NRF). In the CRF volunteers, significant plasma levels (3.0 +/- 1.4 microM) persisted at 47 hours after drug administration (before hemodialysis) whereas in the NRF patients levels dropped to less than 1 microM by 11 hours. Hemodialysis was started 47 hours after infusion and was continued for six hours. The pre-dialysis plasma drug level was reduced by 61.5 percent at 0.25 to 1.5 hours after the end of dialysis. The mean plasma t 1/2 during dialysis of 5.4 hours, the extraction ratio of 0.44, and the dialysis clearance for plasma of 113 ml/min indicate that acyclovir is efficiently removed by hemodialysis. One-half the suggested intravenous dose for a particular indication can be given every 24 hours and a similar replacement dose should be given after each dialysis.

Acyclovir in human breast milk

Acyclovir concentration was measured by radioimmunoassay in the serum and milk of a lactating woman who was treated with oral acyclovir for herpes zoster. Daily serum and milk samples showing milk concentrations that averaged being 3.24-fold higher than serum levels suggest a low infant dose. The elimination phase demonstrated a half-life of 2.8 hours in milk.