Biomedical subjects

G L Drusano

Publications and source records attributed to G L Drusano.

At least 19 recordsLinked to original sources

PubMed1995

Reduction of the in vitro activity of A77003, an inhibitor of human immunodeficiency virus protease, by human serum alpha 1 acid glycoprotein.

Since plasma protein binding of antiinfectives can adversely affect drug activity, the effect of serum proteins on the in vitro antiviral activity of A77003, a human immunodeficiency virus type 1 (HIV) protease inhibitor, was investigated. In vitro, A77003 is effective in both acute and chronic infection in 10% fetal bovine or human serum. As the concentration of human serum was increased to 50%, antiviral efficacy decreased 3- to 6-fold. Purified human alpha 1 acid glycoprotein (alpha 1-AGP) at physiologic concentrations (0.5-2 mg/mL) dose-dependently reduced the antiviral activity of A77003. alpha 1-AGP at 1 mg/mL also antagonized the anti-HIV activity of A77003-zidovudine combinations. Therefore, higher concentrations of HIV protease inhibitors than would be predicted, on the basis of in vitro activity in the absence of physiologic concentrations of binding protein, may be required to effectively limit viral replication in vivo.

Antiviral Agents↗

PubMed1995

Determination of robust ocular pharmacokinetic parameters in serum and vitreous humor of albino rabbits following systemic administration of ciprofloxacin from sparse data sets by using IT2S, a population pharmacokinetic modeling program.

Robust determination of the concentration-time profile of anti-infective agents in certain specialized compartments is often limited by the inability to obtain more than a single sample from such a site in any one subject. Vitreous humor and cerebrospinal fluid are obvious examples for which the determination of concentrations of anti-infective agents is limited. Advances in pharmacodynamics have pointed out the importance of understanding the profiles of drugs in the plasma and in specialized compartments in order to dose the drugs to obtain the best patient outcomes. Advances in population pharmacokinetic modeling hold the promise of allowing proper estimation of drug penetration into the vitreous (or other specialized compartment) with only a single vitreous sample, in conjunction with plasma sampling. We have developed a rabbit model which allows multiple samples of vitreous to be obtained without breaking down the blood-vitreous barrier. We have employed this model to test the hypothesis that robust estimates of vitreous penetration by the fluoroquinolone ciprofloxacin can be obtained from a traditional intensive plasma sampling set plus a single vitreous sample. We studied 33 rabbits which were receiving 40 mg of ciprofloxacin per kg of body weight intravenously as short infusions and from which multiple plasma and vitreous samples were obtained and assayed for ciprofloxacin content by high-performance liquid chromatography. Data were analyzed by the iterative two-stage population modeling technique (IT2S), employing the iterative two-stage program of Forrest et al. (Antimicrob. Agents Chemother. 37:1065-1072, 1993). Two data sets were analyzed: all plasma and vitreous samples versus all plasma samples and the initially obtained single vitreous sample. The pharmacokinetic parameter values identified were used to calculate the percent vitreous penetration as the ratio of the area under the concentration-time curve for the vitreous to that for the plasma. The values identified, 4% penetration for the full data set versus 3% penetration for the single vitreous sample data set, and their corresponding estimates were not statistically significantly different. We conclude that population modeling holds promise for the analysis of penetration of antimicrobiol agents into specialized spaces from which only single samples can be obtained, particularly for patients with whom robust plasma sampling can be performed.

Animals↗

PubMed1995

The pharmacokinetics of meropenem.

Meropenem is a new carbapenem antibiotic which differs chemically from imipenem/cilastatin by having a 1-beta-methyl substitution, providing it with excellent intrinsic stability to human renal dehydropeptidase-I. In addition, an altered 2' side chain enhances its anti-pseudomonal activity. The drug has one identified metabolite, a beta-lactam ring-opened form which is devoid of microbiological activity, as would be expected. The parent compound displays linear pharmacokinetics over a dose range of 250 mg to 2 g. The terminal half-life is approximately 1 hour and the plasma clearance is approximately 15.5 L/h/70 kg. The plasma concentrations after a 1 g dose show a trough concentration (8 hours) of slightly greater than 0.25 mg/L. The renal route is the major clearance pathway for this drug and its metabolite, with renal clearance accounting for approximately 70% of the plasma clearance and there being approximately 70% of an administered dose recovered in the urine as intact parent compound over 12 hours. When combined with metabolite, over 90% of administered radiolabel is recovered in the urine over this 12 hour period. As expected, renal functional impairment alters the clearance of meropenem, but the alteration is predictable. Hepatic functional impairment does not alter drug disposition and no dosing alterations are required here. In summary, meropenem's disposition is similar to that seen for imipenem/cilastatin, except that no renal dehydropeptidase-I inhibitor is required. When evaluated against the background of its excellent profile of in vitro activity, it is clear that this is a drug of great promise which should be extensively evaluated in clinical trials of seriously ill patients with nosocomial infections.

Animals↗

PubMed1994

Optimal sampling theory: effect of error in a nominal parameter value on bias and precision of parameter estimation.

The authors examined the robustness of optimal sampling theory in estimating the parameter values of two different populations of patients receiving a constant rate, half-hour intravenous infusion of theophylline. One population consisted of smokers; the other included nonsmokers. The smoking population was predicted to have a serum clearance approximately 50% greater than the nonsmokers because of an induction of the cytochrome P450 system. After an initial study to provide both patient-specific and population mean parameter values, optimal sampling strategies that were derived from each population (seven sample split designs) and the patient's seven sample and four sample design were determined. A second study was performed with an overall sampling strategy that was superset of all the above strategies. The analysis of all samples served as the reference for the parameter values. Bias and precision of the values determined with each of the optimal sampling sets (seven sample sets based on the "correct" and "wrong" populations, the patient's seven and four sample sets) were determined relative to these reference values. Irrespective of the sample set used for analysis, unbiased and precise parameter estimates, particularly of hybrid parameters were provided. With the patient's four sample set, Vss was significantly biased, but the value of (2.2%) was clinically insignificant. The authors conclude that optimal sampling theory, as implemented in this study, provides robust estimates of important pharmacokinetic parameter values, even when errors of 50% are present in the clearance of the population used to calculate the optimal sampling design.

Adolescent↗

PubMed1994

Impact of dosing schedule upon suppression of a retrovirus in a murine model of AIDS encephalopathy.

We studied the impact of zidovudine (AZT) in Cas-Br-M murine leukemia virus-infected NFS-N mice after administration by once-daily bolus or continuous infusion. While higher peak concentrations of AZT were achieved by once-daily dosing, continuous AZT infusion at 25 micrograms/h maintained levels > 1 microM in plasma and > 0.2 microM in the brain. Continuous infusion provided significantly better viral inhibition, even though total doses were only one-third that of the once-daily therapy group.

AIDS Dementia Complex↗

PubMed1994

Effect of 2',3'-didehydro-3'-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies.

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents.

Cell Line↗

PubMed1994

Quantitative relationships between zidovudine exposure and efficacy and toxicity.

We examined the relationship between the concentrations of zidovudine in plasma given by continuous intravenous infusion to human immunodeficiency virus-positive pediatric patients and a surrogate marker of outcome (measured by the increase in the number of CD4-positive T cells) as well as drug-mediated toxicity (change in granulocyte count). The return of CD4-positive T cells was most strongly related to the number of these cells present at the start of therapy. Drug concentration data added little explanatory power to this relationship, indicating that the effect of zidovudine was near maximal throughout the range of concentrations examined. The change in granulocyte count was significantly correlated with zidovudine concentration both from weeks 1 through 8 and from weeks 8 through 12. These findings imply that it may be wise to stratify phase I antiretrovirus drug trials for the entry level of CD4-positive T cells if pharmacodynamic relationships with this marker as the dependent variable are to be sought. Continued efforts need to be made to derive quantitative relationships between drug exposure and measures of both efficacy and toxicity so that the maximal amount of information is derived from small phase I studies.

CD4 Lymphocyte Count↗

PubMed1993

Pharmacodynamics of antiretroviral chemotherapy.

It has been demonstrated that systemic exposure to antiretroviral agents drives both the therapeutic and the toxic effects seen in clinical trials. Consequently, it is necessary to determine plasma concentrations of drugs and their metabolites (and possibly intracellular concentrations) during the course of Phase 1 and 2 evaluations. It also has been demonstrated that having precise mathematical relationships between exposure and response as well as between exposure and toxicity allows rational selection of drug dose for evaluation in larger Phase 2 and 3 clinical trials. This can be seen with AZT, where the exposure-efficacy relationship is clearly at a plateau by 600 mg/day, while the exposure-toxicity relationship predicts increasing toxicity (and, because of the plateauing of the effect relationship, without better therapeutic response). It can be seen most clearly with ddI, where the exposure-efficacy relationship pointed to longer-term therapy with lower doses ultimately being as efficacious as higher dose therapy. When coupled with the long-term tolerance data for ddI, this led to a prospective prediction of superiority of lower-dose therapy, which was validated later. Finally, some problems with current Phase 1 and 2 trial design have been pointed out, in that bioavailability needs to be recognized explicitly as an important evaluation factor in oral antiretroviral therapy. Perhaps most notably, the importance of initial susceptibility of the virus to the study drug has been suggested by the data of Drusano et al. Clearly, the microbiology of the patient needs to be taken into consideration in the evaluation of Phase 1 and 2 antiretroviral trial results.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗

PubMed1992

Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A phase I trial.

OBJECTIVE: To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, phase I study. SETTING: Two university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis. INTERVENTION: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined. MEASUREMENTS: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state. RESULTS: Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant. CONCLUSIONS: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less.

Administration, Oral↗

PubMed1992

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND: Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS: We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS: During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS: In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Use of nonlinear, mixed-effects modeling for population analysis of ofloxacin: effects of age on oral drug pharmacokinetics.

To compare the effect of age on pharmacokinetics of orally administered ofloxacin, two separate studies were reanalyzed using mixed-effect modeling with the program NONMEM. Subjects were male volunteers, 36 age 65 years or greater and 24 age 18-40 years. The younger group received three 100-mg tablets and the older group received two 200-mg tablets of ofloxacin. Serial blood samples obtained throughout dosing were assayed for drug concentrations using high-performance liquid chromatography. A pharmacostatistical model was developed for the data using mixed-effect modeling with NONMEM. A one-compartment open model with first-order absorption, which included the covariables weight and age, best fit the data. Mean (SE) population values were clearance/F 0.219 (0.009) L/hr/kg, volume of distribution/F 1.50 (0.071) L/kg, and absorption rate constant 2.26 (0.048) hr-1. Older subjects had a 29% lower clearance and 13% lower volume of distribution then the younger subjects.

Administration, Oral↗

PubMed1991

Optimal sampling theory and population modelling: application to determination of the influence of the microgravity environment on drug distribution and elimination.

Newer mathematical techniques such as optimal sampling theory and NON-linear Mixed Effects Modelling (NONMEM) allow the determination of pharmacokinetics and pharmacodynamics in populations of individuals previously believed to be "too ill" or "too difficult to study." Optimal sampling determines the most information-rich times to sample the system, allowing robust parameter estimates to be determined from the minimal number of samples. NONMEM, by taking the population as the unit of analysis, allows even fragmentary patient data sets to contribute to population parameter estimates. Obviously, the microgravity environment presents extreme logistical difficulties to the performance of traditional pharmacokinetic and pharmacodynamic studies. Examples of the validation of these techniques are presented, which indicates their likely utility in the important task of determining the influence of the microgravity environment on drug distribution and elimination, even accounting for the limitations of support which will be faced in this circumstance.

Bayes Theorem↗

PubMed1990

Population pharmacokinetics of zidovudine. The Veterans Administration Cooperative Studies Group.

The epidemic of human immunodeficiency virus infection has forced an unprecedented acceleration of drug development. The lack of effective therapy at present against many of the infectious complications of acquired immunodeficiency syndrome (AIDS) has forced the rapid clinical introduction of new agents. Population pharmacokinetic models are particularly attractive as a means of assessing drug disposition in cohorts different from those studied during necessarily abbreviated phase I trials. We have used the population pharmacokinetics model as implemented by the computer program NONMEM to study the distribution of zidovudine in a large number of patients who have AIDS-related complex and who are therefore at an earlier stage of immunosuppression than subjects in other studies. We confirm a clearance of drug identical to that seen by traditional methods but a larger volume of distribution than estimated previously in patients with AIDS. Possible reasons for this discrepancy and the use of this method in the development of antiretroviral therapy are discussed.

AIDS-Related Complex↗

PubMed1990

Effect of renal function on the bioavailability of ciprofloxacin.

The effect of renal function on the bioavailability of ciprofloxacin was studied in 21 subjects with measured creatinine clearances ranging from 0 to 8.99 liters/h per 1.73 m2. Each subject received ciprofloxacin, 200 mg intravenously and 750 mg orally, separated by at least 1 week. Serial (12 to 15) blood samples were obtained over 24 to 48 h. Concentrations in serum were assayed by high-pressure liquid chromatography. Area under the curve was calculated by the trapezoidal rule with extrapolation to infinity. Bioavailability was calculated as the ratio between the dose-normalized area under the curve of oral and intravenous administrations. The overall mean (standard deviation) bioavailability observed was 63.4% (14.6%), similar to that observed in those with normal renal function (69.0% [15.7%]). The mean bioavailability in the subgroup of subjects with renal insufficiency was 59.9% (13.3%). The observed range in bioavailability was 33.9 to 91.4%. Linear regression did not reveal a correlation between creatinine clearance and bioavailability. Renal insufficiency does not appear to affect ciprofloxacin bioavailability.

Administration, Oral↗

PubMed1990

Human pharmacodynamics of beta-lactams, aminoglycosides and their combination.

In-vitro and animal model data indicate that the time beta-lactam serum concentrations remain above the MIC is an important determinant of the organism kill at the primary infection site. Similarly, for aminoglycosides, area under the curve and peak concentrations have been linked to organism kill and suppression of resistance. It is only in clinical patients that these data can be validated as to their significance. For beta-lactams, little clinical data exist regarding these concepts. However, Bodey & colleagues have shown that profoundly, persistently neutropenic cancer patients fared better when one of their beta-lactams was administered continuously. Our group was able to correctly predict outcome in 9/10 patients bacteremic with a Gram-negative bacillus when receiving a single beta-lactam on the basis of the time free drug concentrations remained above the MIC. Schentag et al studied patients with lower respiratory tract infection treated with cefmenoxime alone and found a significant relationship between time greater than MIC & time to clearance of the pathogen from cultures of the tracheobronchial tree. These data would seem to validate the predictive nature of the findings from in-vitro & animal model studies. With aminoglycosides, Moore, Smith & Lietman were able to demonstrate a highly significant correlation between outcome and the maximal peak concentrations to MIC ratio achieved for patients with single organism Gram-negative rod infections. This is somewhat at variance with some animal models, but as the studies were performed with a fixed dosing interval, the outcome is not surprising. Little has been done with combinations of these agents in patients. Barriere & colleagues have proposed the AUC of the reciprocal serum bactericidal activity curve as a way to integrate the activity of combinations. We have developed a method employing logistic regression analysis to integrate the activity from the administration of multiple agents. The integration of this approach with each drug's pharmacokinetics allows the generation of a plot of the probability of the blood remaining sterile over a steady state dosing interval. This approach has been preliminarily tested in 6 individuals with excellent concordance between outcome and prediction. Development of data in-vitro and in animal models with validation in patients will hopefully provide the impetus to optimize therapy, and thence, outcome for the most seriously ill individuals.

Aminoglycosides↗

PubMed1989

Ciprofloxacin pharmacokinetics in critically ill trauma patients.

The steady-state pharmacokinetics of ciprofloxacin 200 mg intravenously every 12 hours was examined in 10 critically ill trauma patients. The mean parameter estimates for total clearance, renal clearance, non-renal clearance, and volume of distribution were 30.08 liters/hour/1.73 m2, 16.62 liters/hour/1.73 m2, 13.46 liters/hour/1.73 m2, and 2.10 liters/kg. Although the mean values were similar to those previously reported, significant individual differences were observed, with the coefficient of variation ranging from 41 to 61 percent. Non-renal clearance appeared to have a bimodal distribution. The dosage studied appeared to provide adequate serum concentration profiles to treat most pathogens found in infected trauma patients. However, the use of higher doses and more frequent dosing may be required to treat patients with Staphylococcus aureus and Pseudomonas aeruginosa infections.

Adult↗

PubMed1989

Prospective use of optimal sampling theory: steady-state ciprofloxacin pharmacokinetics in critically ill trauma patients.

We examined the use of optimal sampling theory to determine a sparse sampling design to estimate pharmacokinetic parameters of ciprofloxacin in patients who had sustained trauma. Two serum sampling strategies, consisting of six sampling times each, were derived on the basis of the patient's renal function (patients with creatinine clearance greater than or equal to 6 L/hr/1.73 m2 and patients with creatinine clearances less than 6 L/hr/1.73 m2). Two additional serum samples were obtained for other aspects to the study. A timed urine collection was also obtained. Pharmacokinetic parameter estimates were determined by comodeling the serum and urine data with a three-compartment open model (parameterized as microconstants) with a bayesian algorithm and by noncompartmental analysis. Bayesian-derived parameter estimates were total body clearance of drug from plasma, 29.8 L/hr/1.73 m2; renal clearance, 17.0 L/hr/1.73 m2; and nonrenal clearance, 12.7 L/hr/1.73 m2 and were not significantly different from noncompartmentally derived parameters (p = 0.80, p = 0.65 and p = 0.333, respectively). The study demonstrates the use of optimal sampling theory to determine an informative yet relatively sparse sampling strategy for a drug with a complex pharmacokinetic model.

Adult↗