Biomedical subjects

Thaddeus H Grasela

Publications and source records attributed to Thaddeus H Grasela.

7 recordsLinked to original sources

PubMed2005

Challenges in the transition to model-based development.

Practitioners of the art and science of pharmacometrics are well aware of the considerable effort required to successfully complete modeling and simulation activities for drug development programs. This is particularly true because of the current, ad hoc implementation wherein modeling and simulation activities are piggybacked onto traditional development programs. This effort, coupled with the failure to explicitly design development programs around modeling and simulation, will continue to be an important obstacle to the successful transition to model-based drug development. Challenges with timely data availability, high data discard rates, delays in completing modeling and simulation activities, and resistance of development teams to the use of modeling and simulation in decision making are all symptoms of an immature process capability for performing modeling and simulation. A process that will fulfill the promise of model-based development will require the development and deployment of three critical elements. The first is the infrastructure--the data definitions and assembly processes that will allow efficient pooling of data across trials and development programs. The second is the process itself--developing guidelines for deciding when and where modeling and simulation should be applied and the criteria for assessing performance and impact. The third element concerns the organization and culture--the establishment of truly integrated, multidisciplinary, and multiorganizational development teams trained in the use of modeling and simulation in decision-making. Creating these capabilities, infrastructure, and incentivizations are critical to realizing the full value of modeling and simulation in drug development.

Animals↗

PubMed2005

The pharmacokinetic and pharmacodynamic profile of tigecycline.

Tigecycline, a first-in-class expanded-spectrum antimicrobial agent, has demonstrated efficacy in the treatment of complicated intra-abdominal and skin and skin-structure infections. This new antibiotic is available as an intravenous formulation and exhibits linear pharmacokinetics. It is rapidly distributed and has a large volume of distribution, indicating extensive tissue penetration. After a 100-milligram loading dose, followed by 50 milligrams every 12 h, the steady-state maximum concentration in serum after a 1-h infusion is approximately 0.6 microg/mL, the 24-h steady-state area under the concentration-time curve is approximately 5-6 microg.h/mL, and the terminal elimination half-life is approximately 40 h. The major route of elimination of tigecycline is through the feces, primarily as unchanged drug. The pharmacokinetic profile is not affected by severe or end-stage renal disease, nor is it significantly altered by hemodialysis. The pharmacokinetics of tigecycline are also not affected by food, although tolerability is increased if the drug is administered following a meal.

Animals↗

PubMed2005

Pharmacokinetic/pharmacodynamic profile for tigecycline-a new glycylcycline antimicrobial agent.

Tigecycline is a new first-in-class glycylcycline antimicrobial agent with expanded broad-spectrum activity against both Gram-negative and Gram-positive aerobes and anaerobes, as well as atypical bacterial species. The spectrum of activity extends to clinically relevant susceptible and multidrug-resistant strains of Staphylococcus aureus, Streptococcus pneumoniae, vancomycin-resistant enterococci, and Enterobacteriaceae, including extended-spectrum beta-lactamase-producing strains. Tigecycline is administered as an intravenous formulation and has been studied in the treatment of serious polymicrobial infections, including complicated skin and skin-structure infections and intra-abdominal infections. Pharmacokinetic analysis of data from phase 1 trials of healthy subjects indicate that tigecycline has a large volume of distribution, signifying extensive tissue penetration, and a long terminal elimination half-life (approximately 40 h), easily allowing for twice-daily dose administration. Tigecycline penetrates well into blister fluid, which supports the positive findings of phase 2 and 3 studies of the efficacy of tigecycline in the treatment of serious skin and skin-structure infections. Metabolic studies in humans have revealed that tigecycline undergoes very limited metabolism and the primary route of elimination of unchanged drug is through the feces, with glucuronidation and renal elimination as secondary routes. A preliminary pharmacokinetic (PK)/pharmacodynamic analysis in experimental animal models of infection indicates that the efficacy of tigecycline is probably best predicted by the ratio of the area under the concentration-time curve to the minimum inhibitory concentration. The expanded in vitro activity against a broad range of bacteria, including resistant pathogens, and favorable PK profile of tigecycline suggest that this novel antimicrobial agent should offer clinicians an option for the treatment of patients with serious bacterial infections.

Age Factors↗

PubMed2004

The cost-effectiveness of cefepime plus metronidazole versus imipenem/cilastatin in the treatment of complicated intra-abdominal infection.

BACKGROUND: Our objective was to compare the economic benefits of cefepime plus metronidazole with those of imipenem/cilastatin in the treatment of complicated intra-abdominal infections. METHODS: We used a retrospective analysis of clinical outcomes and health resource utilization data collected during a randomized, double-blind, multi-center clinical trial. Seventeen university-affiliated hospitals in the United States and Canada participated, as did 323 patients with complicated intra-abdominal infections. Decision analysis was conducted using a decision node of cefepime vs. imipenem, and chance nodes that included an Acute Physiology and Chronic Health Evaluation (APACHE) II score of #15 versus .15; a need for posttreatment surgical procedures; and clinical outcomes. Effectiveness of treatment was measured by differences in the length and cost of hospital stays, the number and cost of surgical procedures after treatment, cure rates, and the cost of antibiotics. Also evalulated were the incremental costs of cure (i.e., the costs of additional cures). RESULTS: Comparing cefepime plus metronidazole with imipenem/cilastatin, the expected cost of patient care was $8,218 versus $10,414, respectively, and the cost-effectiveness ratio per cure was $10,058 versus $13,685. For severely ill patients (APACHE II score .15), the expected cost was $12,962 versus $23,153, and the cost-effectiveness ratio per cure was $15,321 versus $64,313. CONCLUSIONS: Cefepime plus metronidazole was more cost-effective than imipenem/cilastatin in the treatment of complicated intra-abdominal infections, primarily because of fewer post-treatment surgical procedures and shorter hospital stays. The primary advantage accrued to severely ill patients who had an APACHE II score .15.

APACHE↗

PubMed2004

Population pharmacokinetics and pharmacodynamics of garenoxacin in patients with community-acquired respiratory tract infections.

Garenoxacin (T-3811ME, BMS-284756) is a novel, broad-spectrum des-F(6) quinolone currently under study for the treatment of community-acquired respiratory tract infections. This analysis assessed garenoxacin population pharmacokinetics and exposure-response relationships for safety (adverse effects [AE]) and antimicrobial activity (clinical cure and bacteriologic eradication of Streptococcus pneumoniae and the grouping of Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Data were obtained from three phase II clinical trials of garenoxacin administered orally as 400 mg once daily for 5 to 10 days for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and sinusitis. Samples were taken from each patient before drug administration, 2 h following administration of the first dose, and on the day 3 to 5 visit. Individual Bayesian estimates of the fu (fraction unbound), the Cmax, and the fu for the area under the concentration-time curve from 0 to 24 h (fu AUC(0-24)) were calculated as measurements of drug exposure by using an ex vivo assessment of average protein binding. Regression analysis was performed to examine the following relationships: treatment-emergent AE incidence and AUC(0-24), Cmax, or patient factors; clinical response or bacterial eradication and drug exposure (fu Cmax/MIC, fu AUC(0-24)/MIC, and other exposure covariates); or disease and patient factors. Garenoxacin pharmacokinetics were described by a one-compartment model with first-order absorption and elimination. Clearance was dependent on creatinine clearance, ideal body weight, age, obesity, and concomitant use of pseudoephedrine. The volume of distribution was dependent on weight and gender. Patients with mild or moderate renal dysfunction had, on average, approximately a 16 or 26% decrease in clearance, respectively, compared to patients of the same gender and obesity classification with normal renal function. AE occurrence was not related to garenoxacin exposure. Overall, clinical cure and bacterial eradication rates were 91 and 90%, respectively, for S. pneumoniae and 93 and 92%, respectively, for the grouping of H. influenzae, H. parainfluenzae, and M. catarrhalis. The fu AUC(0-24)/MIC ratios were high (>90% were >200), and none of the pharmacokinetic-pharmacodynamic exposure measurements indexed to the MIC or other factors were significant predictors of clinical or bacteriologic response. Garenoxacin clearance was primarily related to creatinine clearance and ideal body weight. Although garenoxacin exposure was approximately 25% higher for patients with moderate renal dysfunction, this increase does not appear to be clinically significant as exposures in this patient population were not significant predictors of AE occurrence. Garenoxacin exposures were at the upper end of the exposure-response curves for measurements of antimicrobial activity, suggesting that 400 mg of garenoxacin once daily is a safe and adequate dose for the treatment of the specified community-acquired respiratory tract infections.

Adolescent↗

PubMed2003

Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction.

OBJECTIVES: Recently, anecdotal reports via the FDA's MedWatch reporting system have documented rare but serious hyperglycaemia in elderly patients receiving gatifloxacin. One possible factor contributing to these events may be gatifloxacin overexposure, resulting from age-related decreases in renal function in elderly patients predisposed to glycaemic alterations. These analyses examine gatifloxacin exposure in 10 patients with severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic (PK-PD) rationale for a potential age-related dose reduction to avoid high exposures, and evaluate the likely impact of such a dose reduction on clinical efficacy in this specific patient population. METHODS: First, a previously derived population pharmacokinetic model, with patient demographics, was used to estimate gatifloxacin AUC0-24 following a dosage regimen of 400 mg/24 h in 10 index patients with severe hyperglycaemia. Second, the population pharmacokinetic model and patient demographic data from 2696 patients aged > or =65 years from two New Drug Application (NDA) databases were used to estimate AUC0-24 following dosage regimens for gatifloxacin of 200 and 400 mg/24 h. Finally, Monte Carlo simulation was utilized to assess the probability of achieving PK-PD target exposures against Streptococcus pneumoniae in elderly patients using these regimens. RESULTS: The mean estimated AUC0-24 among severe hyperglycaemia cases was 74 mg.h/L (range 57-100). Gatifloxacin AUC0-24 exposures for the 400 mg regimen were predicted to be higher in patients aged > or =65 years and similar to the severe hyperglycaemia cases. The probability of AUC0-24 > or =60 and > or =70 in patients aged > or =65 years for the 200 mg regimen was 0.03 and <0.01, respectively, versus 0.51 and 0.35 for the 400 mg regimen, respectively. The probability of achieving PK-PD target exposures against S. pneumoniae in patients aged > or =65 years receiving the 200 mg regimen was 0.99. CONCLUSIONS: The probability of a patient aged > or =65 years having an AUC0-24 > or =60-70 mg.h/L is markedly lower following a 200 mg regimen relative to a 400 mg regimen, suggesting a decreased risk of severe hyperglycaemia in a predisposed patient. Moreover, a dose reduction does not appear to significantly modify the likelihood of achieving the PK-PD target of gatifloxacin against S. pneumoniae.

Aged↗

PubMed2002

Eliminating intensive postoperative care in same-day surgery patients using short-acting anesthetics.

BACKGROUND: A multidisciplinary effort was undertaken to determine whether patients could safely bypass the postanesthesia care unit (PACU) after same-day surgery by moving to an earlier time point evaluation of recovery criteria. METHODS: A prospective, outcomes research study with a baseline month, an intervention month, and a follow-up month was designed. Five surgical centers (three community-based hospitals and two freestanding ambulatory surgical centers) were utilized. Two thousand five hundred eight patients were involved in the baseline period, and 2,354 were involved in the follow-up period. Outcome measures included PACU bypass rates and adverse events. Intervention consisted of a multidisciplinary educational program and routine feedback reports. RESULTS: The overall PACU bypass rate (58%) was significantly different from baseline (15.9%, P < 0.001), for patients to whom a general anesthetic was administered (0.4-31.8%, P < 0.001), and for those given other anesthetic techniques (monitored anesthesia care, regional or local anesthetics; 29.1-84.2%, P < 0.001). During the follow-up period, the average (SD) recovery duration for patients who bypassed the PACU was significantly shorter compared to that for patients who did not bypass, 84.6 (61.5) versus 175.1 (98.8) min, P < 0.001, with no change in patient outcome. Patients receiving only short-acting anesthetics were 78% more likely (P < 0.002) to bypass the PACU after adjusting for various surgical procedures. CONCLUSIONS: This study represents a substantial change in clinical practice in the perioperative setting. Same-day surgical patients given short-acting anesthetic agents and who are awake, alert, and mobile requiring no parenteral pain medications and with no bleeding or nausea at the end of an operative procedure can safely bypass the PACU.

Adult↗