Paul S. Lietman

Anti-Human Immunodeficiency Virus (HIV) Activity, Safety, and Pharmacokinetics of Adefovir Dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-Infected Patients

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bioavailability, pharmacokinetics, and maximum tolerated dose of HPMPC (cidofovir). Five subjects were randomized to receive drug and two to receive placebo at each of three dosage tier (1, 3, and 10 mg/kg) with a 2-week washout period doses. Subjects at 1 and 3 mg/kg received single doses of HPMPC by subcutaneous (s.c.) intravenous (i.v.), and oral (p.o.) routes, while subjects at 10 mg/kg received only i.v. and p.o. doses. For subjects already taking zidovudine, zidovudine AUC values are determined before and then with HPMPC administration for each route. The AUC values of HPMPC were dose-proportional. Subcutaneous bioavailability was essentially equivalent to that of the intravenous route, but the development of transient local fibrosis ad the volumes needed for subcutaneous dosing precluded higher subcutaneous dosing than 3 mg/kg. Oral bioavailability was poor, estimated to be less than 5%. Drug elimination was predominantly renal. Nephrotoxicity in one subject was the only serious adverse event observed. This subject had a significant lag period prior to oral absorption and also had the highest AUC values for both HPMPC and zidovudine. We found no consistent effect on zidovudine AUC concomitant HPMPC.

A double-blind controlled trial of anti-Pseudomonas chemotherapy of acute respiratory exacerbations in patients with cystic fibrosis

A double-blind controlled trail of anti-Pseudomonas chemotherapy was carried out in 24 exacerbations of pulmonary disease in patients with cystic fibrosis. Fifteen exacerbations were treated with oxacillin plus sisomicin and carbenicillin (treatment group); nine were treated with oxacillin alone (control group). The planned length of treatment was 14 days. The difference between the failure rate in the treatment group (3/15) and the control group (7/9) was statistically significant (P less than 0.015). The difference in improvement of forced expiratory volume in 1 second was also significant (P less than 0.025). At the end of the study, Pseudomonas aeruginosa was still present in the sputum of all nine patients in the control group, but was not isolated from six of the 15 patients in the treatment group. The data suggest a beneficial role for anti-Pseudomonas chemotherapy in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

Herpes simplex-1 virus thymidine kinase gene is unable to completely eliminate live, nonimmunogenic tumor cell vaccines

Recent experiments with genetically engineered tumors have generated renewed interest in active cellular immunotherapy as a cancer treatment modality. In order to consider the use of live tumor cells for immunotherapy in human cancer patients, it will be important to ensure that these cells do not themselves produce morbidity in the event the immune system fails to eliminate them. Toward this end, we have examined a strategy for eliminating genetically manipulated nonimmunogenic tumors in vivo. When B16F10 melanoma cells were transfected with the Herpes simplex virus 1 thymidine kinase (HSV-TK) gene, cells were rendered susceptible to killing by the nucleoside analogs acyclovir (ACV) and ganciclovir (GCV). B16-HSV-TK+ tumors established in C57BL6 mice were successfully suicided in vivo when GCV was administered by continuous infusion. However, late recurrences were observed even after 1 month of continuous GCV treatment. In vivo growth kinetics suggested that the recurrences resulted from a tiny number (< 20) of cells that had survived the GCV treatment. Interestingly, recurrent tumors were as sensitive to GCV as the parental B16-HSV-TK+ line. While these results demonstrate potential feasibility of the suicide gene strategy for active immunotherapy with live tumor cells, they also illustrate that approaches dependent on the intracellular generation of cell cycle-dependent toxins may fail to eliminate small numbers of cells that temporarily exit cell cycle or that are pharmacologically sequestered.

The pharmacokinetics of amikacin in children

The pharmacokinetic variables of amikacin were measured in 20 children and adolescents, four to 16 years of age. The mean plasma clearance of amikacin was 120 ml/minute/1.73 m 2 . The major route of elimination was renal (82%). Simultaneously measured inulin clearance showed that a majority (64%) of the drug filtered by the kidneys was excreted in the urine. The mean volume of distribution of amikacin was 32% of body weight; half-life during the final (pseudoequilibrium) phase averaged 1.6 hours. No significant accumulation of the drug was seen when four doses were given intravenously at 420 mg/m 2 every 8 hours; the plasma concentration just before injection of the fourth dose averaged 2.4±1.1 μg/ml. The mean plasma concentration at 60 to 75 minutes after injection of the drug was 28.7 μg/ml with little interpatient variation (SD 3.5 μg/ml). When the dose was expressed in terms of milligrams per kilogram, it was found that children often needed 50 to 100% more of the drug, compared to adults, to achieve equivalent plasma concentrations; this larger requirement was primarily due to a higher clearance of amikacin in proportion to body weight. Dosages based on surface area, however, resulted in uniform requirements and predictable plasma concentrations in all patients studied.

Netilmicin and gentamicin multidose kinetics in normal subjects.

Multidose netilmicin and gentamicin kinetics were studied in 20 healthy subjects who received 1.7 mg/kg gentamicin (n = 10) or netilmicin (n = 10) as a 20‐min infusion every 8 hr for 10 days (28 doses) during a randomized, double‐blind comparative trial designed to study adverse effects and kinetics of netilmicin and gentamicin. Multidose kinetics were of the same order for gentamicin and netilmicin with the exception of the terminal plasma t½ (94 and 156 hr) and the volume of distribution at steady state (450 and 1072 ml/kg). Mean peak plasma concentrations of netilmicin were slightly lower than gentamicin. Percentage of the dose eliminated in urine did not differ for the two aminoglycosides. Aminoglycoside was detectable in plasma and continued to be eliminated in urine for at least 6 days after the final dose. The plasma concentration‐time profiles for both netilmicin and gentamicin were well fitted with the sum of three exponential terms; urinary excretion rates‐time plots showed biexponential decay. None of the subjects had any auditory, vestibular, or renal toxicity. Although the data confirm a deep tissue compartment, they suggest that the kinetic processes involved may be more complex than previously supposed.

Biologic response (antiviral) to recombinant human interferon alpha 2a as a aunction of dose and route of administration in healthy volunteers

The kinetics of the antiviral effect of intramuscular and intravenous injections of recombinant human interferon α2a were investigated in healthy volunteers. Cohorts of eight to 11 subjects received single intramuscular injections of either 0.3 × 106, 3 × 106, or 18 × 106 U or an intravenous infusion of 18 × 106 U over 30 minutes. Serial samples of peripheral blood mononuclear cells were analyzed for antiviral effects including both (2‐5) oligoadenylate synthetase activity and resistance to vesicular stomatitis virus infection in vitro. A dose‐response relationship was established between recombinant human interferon α2a dose and both vesicular stomatitis virus resistance and (2‐5) oligoadenylate synthetase activity. At the 0.3 × 106 U dose an antiviral effect occurred without clinical side effects. The presence of clinical side effects is not necessary for an antiviral effect.

Antiviral activity of inhibitors of pyrimidine de-novo biosynthesis

Evaluation of the elevation of host cell biosynthesis of deoxynucleoside triphosphates (dNTPs) induced by human cytomegalovirus (HCMV) infection as a target for antiviral therapeutics was carried out. The concentrations of all four intracellular dNTPs rose rapidly following HCMV infection, and were markedly above baseline by 8 h post infection (p.i.). All four deoxynucleoside triphosphates remained elevated above baseline for at least 72 h p.i. The effects of inhibitors of the de-novo pathway of pyrimidine biosynthesis on HCMV viral replication-were quantified by DNA dot blot. All pyrimidine biosynthesis inhibitors examined inhibited the HCMV DNA replication at concentrations that were non-toxic to the cell. These drugs were also more effective against HCMV, which is highly dependent on host denovo synthesis, than against HSV-1 which encodes enzymes capable of increasing the supply of dNTPs. The antiviral effect of brequinar, an inhibitor of one of the enzymes of the de-novo pathway (dihydroorotate dehydrogenase), was examined to determine if it coincided with a decrease in dNTPs. HCMV-infected fibroblasts and uninfected control cells were treated with a concentration of brequinar able to inhibit HCMV DNA levels 90%. It was found that brequinar markedly lowered the levels of dTTP found in treated cells compared to untreated cells in both HCMV-infected and uninfected cells.

Clinical pharmacology: Foscarnet

Foscarnet exerts its antiviral effects via reversible inhibition of viral polymerases. Pharmacodynamic data indicate that herpesvirus and human immunodeficiency virus replication is inhibited by therapeutically achievable concentrations of foscarnet; however, the concentrations of foscarnet required for such inhibition have been found to vary widely. Pharmacokinetic data indicate that foscarnet is eliminated via the renal route, undergoes negligible metabolism, and appears to be distributed widely from the circulation. However, the available data indicate that the pharmacokinetics of the drug varies among patients and within the individual patient, particularly with regard to plasma drug levels; furthermore, such factors as the intracellular kinetics of the drug have yet to be well characterized. It is thus difficult to formulate optimal dosing regimens on the basis of what is known of foscarnet pharmacodynamics and pharmacokinetics. Nevertheless, dosages that produce clear-cut therapeutic benefits without unacceptable toxicity have been identified in clinical trials of foscarnet in acquired immunodeficiency syndrome (AIDS) patients with cytomegalovirus (CMV) retinitis.

A study of potential vestibulotoxic effects of once daily versus thrice daily administration of tobramycin

Tobramycin 5.1 mg/kg/day was administered for 9 days to 20 healthy human volunteers to determine the potential vestibulotoxicity of once daily versus thrice daily treatment regimens. Vestibular function was tested carefully before, during, and following drug administration, using a battery of postural and caloric tests.