John G. Gambertoglio

Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients: A review

Limited information is available on the pharmacokinetics and bioavailability of prednisone and prednisolone in patients with different disease states. This is partly due to difficulty in measuring these drugs in biological fluids at the usual dosages prescribed to patients. This article attempts to comprehensively review these studies categorized under the following four sections: (1) bioavailability—healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of antacids, effect of food, effect of other drugs (aminophylline, cholestyramine); (2) pharmacokinetics—healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of other drugs, enzyme induction of steroids and the effect on the kinetics of steroids and other drugs; (3) protein binding; and (4) analytical methods. The literature is reviewed through August 1979.

Effect of Food on the Pharmacokinetics of Cyclosporine in Healthy Subjects Following Oral and Intravenous Administration

The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg−1) and intravenously (4 mg kg−1) without and with high fat meals. Both blood and plasma samples (separated at 37°C) were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr−1 Kg−1, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg−1, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine was estimated to be 21 and 79%, when administered without and with a high fat meal, respectively. When cyclosporine was administered intravenously together with a high fat meal, both clearance and volume of distribution increased significantly. Blood and plasma clearances of cyclosporine were 0.44 and 0.70 L hr−1 Kg−1, respectively, when cyclosporine was administered along with a high fat meal. We conclude that food not only enhances the absorption of cyclosporine but also enhances its clearance and volume of distribution. The observed variability in clearance, bioavailability, and volume of distribution values for cyclosporine across various pharmacokinetic studies can be partially accounted by the type of food administered and the sampling matrix used for analysis.

Kinetics of oral ethambutol in the normal subject

Six normal adult volunteers received 15 mg/kg of ethambutol (EMB) by mouth, once as an aqueous solution and again as the commercial tablet preparation. Each dose was separated by at least 7 days. Plasma and urine samples were collected at regular intervals for up to 24 and 72 hr, respectively. Peak plasma concentrations ranged from 3.25 to 5.62 mcg/ml, 2 to 4 hr after tablet dosing. Earlier peak times were found after administering the solution. For plasma concentrations up to 12 hr there was a distinct distribution phase followed by an apparent elimination phase with a mean half‐life (t½) (±SD) of 4.06 ± 0.53 and 4.78 ± 0.41 hr for the tablet and the solution, respectively. Excretion rate plots exhibited similar t½values for the apparent elimination phase. An even longer tV2 of approximately 10 hr was evident from 24‐hr plasma samples and urinary excretion measurements up to 72 hr. Unchanged drug excreted in the urine averaged 61.1 ± 3.8 % of the dose for the tablet and 63.4 ± 2.6 % for the solution. Plasma protein binding for ethambutol determined by equilibrium dialysis and ultrafiltration was approximately 20% to 30%. The concentration ratio of ethambutol in erythrocytes to plasma ranged from 1.1 to 1.6.

The safety and pharmacokinetics of GLQ223 in subjects with AIDS and AIDS-related complex: a phase I study.

A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

Safety, activity, and pharmacokinetics of GLQ223 in patients with AIDS and AIDS-related complex.

GLQ223 is a highly purified single-chain ribosome-inactivating protein with selective effects against a variety of cells, including macrophages infected with human immunodeficiency virus. We evaluated the safety, pharmacokinetics, and immunologic effects of multiple doses of GLQ223 in 22 patients with AIDS or AIDS-related complex; CD4+ T-cell counts were between 100 and 350/mm3. GLQ223 was administered intravenously at doses of 8, 16, 24, 36, and 50 micrograms/kg of body weight; the drug was administered by constant infusion over 3 h to achieve a concentration in serum of 50 ng/ml; this concentration is known to be associated with anti-HIV effects in vitro. All patients reported a flu-like syndrome characterized by muscle and joint aches and an increase in creatinine kinase levels; symptoms were controlled easily. For patients who received 36 and 50 micrograms/kg, target concentrations in serum were achieved and an increase in CD4+ and CD8+ T cells was sustained; this sustained increase persisted for at least 28 days after the last infusion. beta 2-Microglobulin levels increased during the infusions and then declined when the infusions ended. Repeat infusions of GLQ223 were safe and relatively well tolerated. The target concentration of GLQ223 in serum was achieved and sustained. Our results suggest that GLQ223 may have activity in treating patients with human immunodeficiency virus infection.

Comparative study of bioavailabilities and pharmacokinetics of clindamycin in healthy volunteers and patients with AIDS.

The absolute oral bioavailability and pharmacokinetics of clindamycin administered to 16 healthy volunteers and 16 patients with AIDS were compared. Clindamycin was given intravenously (i.v.) (Cleocin phosphate) at a dose of 600 mg as a 25-min infusion and orally (Cleocin hydrochloride) by use of a crossover design in both study groups. Plasma samples were analyzed by gas-liquid chromatography. Plasma drug clearance and volume of distribution at the steady state following the i.v. dose differed between study groups. The clearances were 0.27 +/- 0.06 liter/h/kg in healthy volunteers and 0.21 +/- 0.06 liter/h/kg in AIDS patients (P = 0.014; Mann-Whitney U test); the volumes of distribution at the steady state were 0.79 +/- 0.13 and 0.66 +/- 0.12 liter/kg in healthy volunteers and AIDS patients, respectively (P = 0.005). The elimination half-life did not differ between the two groups. The bioavailability of clindamycin capsules in AIDS patients was approximately 1.5 times that in healthy volunteers (0.53 +/- 0.14 versus 0.75 +/- 0.20; P = 0.002). Peak concentrations following the oral dose were higher in AIDS patients as well (7.7 +/- 2.5 versus 5.3 +/- 1.0 mg/liter; P = 0.0008). Three AIDS patients experienced severe diarrhea following the oral dose; four patients had mild diarrhea following the i.v. dose. No adverse effects were reported by the healthy volunteers. The pharmacokinetic parameters observed in this study for AIDS patients may be useful for the consideration of clindamycin dosage regimens in patients treated for toxoplasmic encephalitis. These findings suggest that the effect of AIDS on drug disposition deserves further investigation, particularly for orally administered drugs.

Disposition kinetics of ethambutol in man

Six normal adult volunteers were administered 15 mg/kg of ethambutol (EMB) by a constant-rate 1-hr infusion. Plasma and urine samples were collected up to 24 and 72 hr, respectively. Peak plasma levels following the 1-hr infusion ranged from 11.6 to 15.4 μg/ml. Subsequent postinfusion EMB levels exhibited multiphasic decay. In the 12-hr period following infusion, EMB levels showed biexponential decay. However, 24-hr plasma levels in all subjects were observed to be higher than those predicted using a two-compartment body model. The α phase in these subjects had a mean half-life of 8.6 min while the half-life of the β phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the γ phase estimated from plasma data points between 12 and 24 hr averaged 11.2±3.6 hr. A terminal γt1/2 of 15.4±1.7 hr was calculated from 12–72 hr urine data. The mean value for the steady-state volume of distribution using a noncompartmental method was 3.89 liters/kg. Plasma EMB clearance ranged from 7.47 to 9.87 ml/min/kg (mean 8.57). The fraction of the dose eliminated unchanged varied from 0.75 to 0.84 (mean 0.79). Renal clearance ranged from 5.93 to 8.45 ml/min/kg (mean 6.81), indicating active tubular secretion.

Pharmacokinetic Evaluation of Hemodialysis in Acute Drug Overdose

The contribution of hemodialysis to the removal of drugs in the overdosed patient continues to be questioned. Often the value of hemodialysis is judged on qualitative rather than quantitative information. The latter information can be obtained by applying pharmacokinetic principles. The primary pharmacokinetic parameters required to evaluate drug removal by hemodialysis are (1) apparent volume of distribution, (2) dialysis clearance, and (3) total body clearance. Eighteen drugs commonly encountered in the overdose setting are evaluated using this approach.

Pathophysiology and Treatment of Clinically Resistant Cytomegalovirus Retinitis

PURPOSE To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. METHODS Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir. RESULTS Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy. CONCLUSION Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.

Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers.

The effect of protein binding on antibiotic efficacy is controversial. The pharmacologic effect of an antibiotic is believed to be related to its unbound concentration at the site of infection. It is unknown whether antibiotics with a low degree of serum protein binding are clinically superior to antibiotics that are highly protein bound. In a randomized, crossover investigation, the serum bactericidal activities of a single dose of ceftazidime (30 mg/kg) and cefoperazone (30 mg/kg) were studied in six healthy volunteers against three clinical isolates of Pseudomonas aeruginosa for which both antibiotics had similar MICs and MBCs. Serum samples were collected over 12 h. The total and unbound antibiotic concentrations were determined by high-pressure liquid chromatography. Mean peak total concentrations of ceftazidime and cefoperazone in serum were 101.7 +/- 18.6 and 264.1 +/- 149.6 micrograms/ml, respectively. Due to its lower protein binding (21 +/- 6%), ceftazidime had significantly higher unbound concentrations in serum than did the highly bound cefoperazone (91.5 +/- 2%). Mean peak unbound concentrations were 78.5 +/- 12.5 and 24.2 +/- 17.8 micrograms/ml for ceftazidime and cefoperazone, respectively. The unbound concentration of ceftazidime at each sampling time was higher than that of cefoperazone. Although total concentrations were consistently higher than the MICs, serum containing cefoperazone showed minimal bactericidal activity against the isolates. In contrast, despite lower total concentrations, ceftazidime had greater antibacterial activity than cefoperazone. Serum bactericidal activity was more closely related to unbound rather than total antibiotic concentrations. Our data support the concept that only the unbound drug is microbiologically active.