Pharmacokinetics and safety of high-dose oral acyclovir for suppression of cytomegalovirus disease after renal transplantation.

The pharmacokinetics and safety of high-dose oral acyclovir for suppression of cytomegalovirus disease were evaluated in 12 patients undergoing renal transplantation. A 12-week course beginning 24 hours before transplantation was administered in doses of 800 to 3200 mg/day based on renal function. Acyclovir plasma concentrations were measured by RIA on posttransplant days 1 or 2 and 5, 6, or 7. Mean peak and trough concentrations on days 5, 6 or 7 were 25 and 18 mumol/L, respectively. The pharmacokinetic model predicted acyclovir concentrations with a precision of 4.1 mumol/L and bias of -1.19 mumol/L. Estimates of individual pharmacokinetic parameters were consistent with literature and a priori values. Two of six adverse events were attributable to acyclovir; both resolved with dose modification. The dosage adjustment scheme and pharmacokinetic model performed well, allowing us to safely administer high-dose oral acyclovir immediately after renal transplantation. We are proceeding with a placebo-controlled study to assess efficacy for suppression of posttransplant cytomegalovirus disease.

Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex.

Zidovudine was present in the semen and serum of six patients with acquired immunodeficiency syndrome or the related complex who were receiving 200 mg of the drug orally every four to six hours. Mean semen zidovudine levels (as measured by a new radioimmunoassay) in samples collected 0.75 to 1.25 hours after oral dosing were 3.63 to 7.19 mumol/L. Levels in semen samples collected 3.0 to 4.5 hours after oral dosing were 1.68 to 6.43 mumol/L. These values are above the in vitro minimum inhibitory concentration for the human immunodeficiency virus type 1 (HIV-1). Mean serum concentrations at the early and late times after oral dosing were 0.22 to 3.07 mumol/L and 0.10 to 1.42 mumol/L, respectively. Ratios of semen/serum zidovudine levels ranged from 1.3 to 20.4. It is possible that a pH-dependent trapping mechanism, which has been described in the prostate for other antibiotics, was responsible for the relatively high semen levels observed.

Ganciclovir treatment of cytomegalovirus disease in transplant recipients and other immunocompromised hosts.

Thirty-one immunocompromised patients with severe cytomegalovirus (CMV) disease were treated with intravenous ganciclovir. Twenty-one patients had received transplants--15 bone marrow recipients, five renal allograft recipients, and one liver transplant recipient--while the other ten were immunocompromised due to acquired immunodeficiency syndrome (six), hematologic malignancies (three), and systemic lupus erythematosus (one). They presented with one or more of the following syndromes: CMV pneumonitis (19), CMV of the gastrointestinal tract (six), CMV retinitis (seven), and CMV hepatitis (three). Seventeen (55%) of 31 patients demonstrated clinical improvement during ganciclovir therapy, with the best response seen in the transplant recipients. Viremia ceased in 14 (93.3%) of 15 patients after a mean of 4.7 days of therapy; viruria ceased in eight (53.3%) of 15 patients after a mean of 11 days of therapy. Ganciclovir plasma concentrations at a dosage of 2.5 mg/kg/three times a day were as follows: mean peak, 16.04 mumol/L; mean trough, 2.38 mumol/L. Neutropenia occurred in 11 (35%) of 31 patients and in nine (60%) of 15 bone marrow transplant recipients. We conclude that ganciclovir exerted an antiviral effect against CMV and may play a role in the treatment of CMV disease in patients with depressed immunity, especially bone marrow and organ transplant recipients.

Serum is an acceptable specimen for measuring acyclovir levels.

Acyclovir levels to date have been performed on plasma rather than serum samples. To determine if serum was an acceptable specimen, acyclovir levels were measured on simultaneously collected plasma and serum samples by radioimmunoassay. Eighty-two paired samples from 20 patients containing between 0.39 and 115.3 microM acyclovir were studied. Least squares regression, orthogonal regression, and two-way analysis of variance with replication all indicated an acceptably high degree of correlation. We concluded that serum is a suitable specimen for measuring acyclovir levels.

Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS.

A patient with acquired immune deficiency syndrome with bilateral cytomegalovirus retinitis was treated with intravitreal 200-micrograms/0.1-ml doses of ganciclovir (9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine). The ganciclovir serum and intravitreal concentrations were measured with an enzyme-linked immunosorbent assay and pharmacokinetic factors were determined. There was no evidence of systemic absorption of ganciclovir from the eye. The elimination half-life of ganciclovir from the vitreous was estimated to be 13.3 hours. The intravitreal concentration remained above the ID50 of cytomegalovirus for approximately 62 hours after a single injection. Clinically, the patient retained useful vision in his right eye for three months. A total of 28 intravitreal injections were given on an outpatient basis under topical anesthesia and were well tolerated. There was no evidence of retinal toxicity from the drug.