Biomedical subjects
Publications and source records attributed to P de Miranda.
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.
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Ganciclovir is a nucleoside analog which inhibits the replication of herpesviruses in vitro and which has been effective by intravenous administration for the treatment of severe cytomegalovirus infection in immunocompromised patients. Because most patients with acquired immunodeficiency syndrome and severe cytomegalovirus infection have required lifelong daily suppressive ganciclovir therapy to control disease progression, oral therapy appears to have practical advantages. We studied the pharmacokinetics of orally administered ganciclovir in four patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Repeated oral ganciclovir doses (10 to 20 mg/kg every 6 h) were well tolerated. With a 20-mg/kg dose given every 6 h, mean steady-state peak and trough levels were 2.96 and 1.05 microM, respectively, and the area under the concentration-time curve from 0 to 24 h was 47 microM X h. Calculated absorption was 3.0%, based on urinary excretion. Because the levels achieved in serum with oral ganciclovir approximated those required to inhibit cytomegalovirus in vitro, a trial of oral maintenance therapy in immunocompromised patients with severe cytomegalovirus infections seems warranted.
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The pharmacokinetics of the antiviral drug 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis. Biexponential decay with a mean distribution t1/2 of 0.23 hours and terminal t1/2 of 2.53 hours was observed. Total clearance correlated well with and exceeded creatinine clearance by a factor of 2.4. Mean volume of the central compartment was 15.26 L/1.73 m2 and the volume of distribution at steady state was 32.8 L/1.73 m2. Peak (model predicted) and trough plasma concentrations were 4.75 to 6.20 micrograms/ml and less than 0.25 to 0.63 microgram/ml, respectively, in patients receiving 2.5 mg/kg. Peak concentrations are well above those needed to inhibit HCMV at the 50% level (ID50) and troughs are near this ID50. Cerebrospinal fluid concentrations of DHPG indicate a penetration of 24% to 67%. No accumulation of DHPG was apparent in these patients. However, dosage reduction is necessary in renal insufficiency. Neutropenia occurred in one patient. The plasma concentration profile of DHPG suggests potential beneficial activity against HCMV.
Substantial levels of acyclovir were detected in the aqueous and vitreous of New Zealand rabbits at various time intervals following subconjunctival injection. Intravitreal penetration of acyclovir after topical application was poor.
9-[(2-hydroxyl-1-(hydroxymethyl)ethoxy]methyl)guanine (hydroxyacyclovir) is a nucleoside analogue with a high degree of efficacy against herpes simplex virus types 1 and 2 and cytomegalovirus (CMV). This antiviral agent demonstrates a low toxicity towards uninfected cells. Intraocular levels in rabbits were evaluated following subconjunctival, intravenous, intravitreal and topical administration. Retinal toxicity studies were performed. Hydroxyacyclovir may have applications in the treatment of deep herpetic infections, CMV retinitis, and acute retinal necrosis.
Clearance studies in rabbits following intravitreal injection of 400 micrograms of 9-([2-Hydroxy-1-(hydroxymethyl)ethoxy]methyl) guanine demonstrated levels of the antiviral at 60 hours above the in vitro ID50 for several strains of human cytomegalovirus. Intravitreal administration of this new antiviral may have therapeutic application in the treatment of acute retinal necrosis and cytomegalovirus retinitis complicating acquired immune deficiency syndrome (AIDS).
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.
Cytomegalovirus infections can cause significant morbidity and mortality in immunosuppressed patients, and present antiviral agents have had little efficacy against these infections. We describe the use of an acyclic nucleoside 9-[2-hydroxy-1-(hydroxymethyl) ethoxy methyl]guanine (BW B759U), in the treatment of two patients with cytomegalovirus retinitis. The efficacy of this agent was evident, with healing of retinal lesions and resolution of viremia and viral shedding. BW B759U appears to be similar pharmacokinetically to intravenous acyclovir in terms of half-life, peak serum levels, and renal excretion.
Acyclovir [9-[(2-hydroxyethoxy)methyl]guanine] is an acyclic guanine nucleoside analogue that is widely used clinically as an antiherpetic agent. Its limited absorption in humans after oral administration prompted the search for prodrugs. A congener, referred to as 6- deoxyacyclovir [2-amino-9-[(2-hydroxyethoxy)methyl]-9H-purine], was synthesized and found to be 18 times more water soluble than was acyclovir. Surprisingly, this congener was readily oxidized to acyclovir by xanthine oxidase (EC 1.2.3.2). It was also oxidized by aldehyde oxidase (EC 1.2.3.1) largely to 8-hydroxy-6- deoxyacyclovir [2-amino-8-hydroxy-9-[(2-hydroxyethoxy)methyl]-9H-purine] and then to 8- hydroxyacyclovir [2-amino-6,8-dihydroxy-9[(2-hydroxyethoxy)methyl]-9H-purine]. 6- Deoxyacyclovir and the major products of its oxidation by aldehyde oxidase lacked appreciable activity against herpes simplex type I in vitro. On the basis of these results, it was apparent that the success of 6- deoxyacyclovir as a prodrug in vivo would depend upon how well its desired activation by xanthine oxidase competed with the nonactivating oxidations by aldehyde oxidase. In rats dosed orally with 6- deoxyacyclovir , absorption was extensive and the major urinary metabolite was acyclovir. In two human volunteers, urinary excretions of acyclovir were 5-6 times greater than those typically observed after administration of equivalent doses of acyclovir itself. The areas under the plasma concentration-time curves for acyclovir were also 5-6 times greater. Plasma levels of acyclovir peaked soon after ingestion of the prodrug, indicating rapid absorption and metabolic conversion. These results suggested that 6- deoxyacyclovir might have clinical usefulness as a prodrug of acyclovir suitable for oral administration.
Acyclovir pharmacokinetics has been extensively investigated during the various phases of clinical development. Most of the administered drug is eliminated from the body unchanged, via the kidneys by glomerular filtration and tubular secretion. After intravenous dosing of patients with normal renal function, 8 to 14% of the dose is recovered in the urine as the metabolite 9-carboxymethoxymethylguanine. Adequate distribution of acyclovir has been demonstrated in the cerebrospinal fluid, vesicular fluid, vaginal secretions and tissues. The low plasma protein binding of acyclovir precludes drug interactions involving binding displacement. When intravenous doses in the range of 2.5 to 15 mg/kg were given every 8 h to adult patients, dose-independent kinetics was observed. Continuous infusions of acyclovir over an equivalent daily dose range have achieved predictable plasma levels. Acyclovir half-life (T1/2 beta) and total body clearance (Cltot) are influenced significantly by renal function, and dosage adjustments should be made for patients with impaired renal function. For patients with normal renal function (creatinine clearance (Clcr) greater than 80 ml/min/1.73m2) mean T1/2 beta and Cltot were 2.5 h and 327 ml/min/1.73 m2, respectively. In children 1-year-old or older, Cltot normalized by body surface area was essentially the same as in adults with normal renal function, whereas Cltot for neonates was approximately one-third the adult value. In the adult population, age-related decreases in acyclovir Cltot reflect age-related changes in renal function; therefore dosage adjustments based on Clcr will compensate for age effects on acyclovir pharmacokinetics. After oral administration, the bioavailability of acyclovir was approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
2,6-Diamino-9-(2-hydroxyethoxymethyl)purine (A134U), the 6-deoxy-6-amino analog of the antiviral agent acyclovir (ACV), was administered orally to dogs and rats. Plasma concentration-time profiles and urinary excretion of A134U and its deamination product, ACV, were determined. Mean peak plasma ACV concentrations achieved in the dog were 57, 156 and 285 microM after A134U doses of 20, 50 and 120 mg/kg, respectively, and increased in near proportion to the dose. The urinary recovery of ACV accounted for 60-92% of the two lower doses, but only 40-58% of the highest dose. In the rat, peak plasma ACV concentrations were 3.1 and 10.7 microM, respectively, after 20- and 50-mg/kg doses of A134U. After 5- and 20-mg/kg oral doses of [2-14C]A134U, the urinary recovery of ACV (20-27%) accounted for 59 to 76% of the absorbed dose. The remainder was excreted largely as unchanged A134U, with negligible (0.4-1.3%) biotransformation to inactive metabolites. Except for small decreases in absorption and increases in deamination, no change in the metabolism of A134U was observed after its repeated oral administration to rats. Oral dosing of dogs and rats with A134U resulted in peak plasma concentrations and total urinary recoveries of ACV greater than those observed after equivalent oral doses of ACV, suggesting that A134U might be an effective prodrug of ACV for use in the oral therapy of herpes simplex virus infections.
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.
Two guinea pigs and two rabbits were each inoculated subcutaneously with 14C-labeled acyclovir (25 mg/kg). Both species excreted the entire amount within 72 hours. The rabbits excreted all of the radioactivity in the urine while the guinea pigs excreted an average of 14.2 percent in the feces. The rabbits excreted an average of 71.0 percent of the dose as unchanged drug; 25.1 percent was excreted as 9-carboxymethoxymethylguanine (CMMG) and 3.5 percent as 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine (8-hydroxyacyclovir). An average of 60.7 percent of the dose was recovered from the guinea pigs as acyclovir; 32.3 percent was excreted as CMMG and 3.1 percent as 8-hydroxyacyclovir. The two rabbits showed elimination-phase half-lives (t 1/2 beta) for plasma acyclovir of 0.8 and 2.2 hours. Mean t 1/2 beta for acyclovir in two rhesus, four patas, and four african green monkeys, each receiving acyclovir (10 mg/kg) as a bolus intravenous injection, were 1.2, 1.7, and 1.8 hours respectively. The average 48 hour urinary excretion of acyclovir, 8-hydroxyacyclovir, and CMMG in the rhesus monkey was estimated to be 21.3 percent, 15.3 percent, and 7.1 percent, respectively, of the total administered amount. The patas and african green species excreted the dose mostly as acyclovir and CMMG.
The effect of oral or intraperitoneal administration of acyclovir was evaluated in four experimental models of herpes simplex virus (HSV) encephalitis in mice. Mice were inoculated with HSV-1 or HSV-2 intracerebrally or with HSV-2 intranasally, intraperitoneally, or intravaginally. With all four routes of inoculation, oral acyclovir therapy significantly reduced mortality when started as late as 72 to 96 hours after viral challenge. Intraperitoneal acyclovir was not effective in protecting mice inoculated intravaginally, but was effective if given 24 to 48 hours after intracerebral or intranasal challenge and as late as 96 hours after intraperitoneal infection. Oral acyclovir was more active than intraperitoneal treatment in all four model infections. Levels of acyclovir inhibitory for HSV in cell culture were maintained in plasma and brain tissue throughout oral treatment but lasted only three to six hours after each intraperitoneal treatment. These results suggest that acyclovir may be useful in treating serious HSV infections in humans.
Data are reported from three step-wise pharmacokinetic studies in 43 patients who received acyclovir. Dosage regimens began at 0.5 mg/kg administered as a single dose intravenously and were increased to 15 mg/kg per dose given three times daily for five days. All patients evaluated were immunocompromised by underlying disease or received cytolytic and/or cytotoxic therapy. Patients with virologically confirmed herpes simplex or zoster infections were assessed in the multiday, multidose pharmacokinetic trial. Postinfusion plasma concentrations of acyclovir declined in a biphasic manner such that the plasma-concentration time data were fitted by a two-compartment, open-model with zero-order input. The drug's half-life showed little variation with a mean of 3.16 +/- 0.20 hours. In both single-dose and multiple-dose studies there was dose proportionality with peak plasma levels and area under the plasma concentration-time curve indicating dose-independent pharmacokinetics. The kidney was the principal route of drug clearance with a mean recovery of 60 +/- 12 percent. Renal clearance exceeded creatinine clearance indicating renal tubular secretion of drug. No significant clinical or laboratory evidence of toxicity appeared. These studies provide a foundation for the evaluation of acyclovir in controlled trials.
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.