Julie A. Passarell

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

ABSTRACT Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Intra-Abdominal Infections

ABSTRACT Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono- or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/MIC ratio was also borderline predictive of microbiological response (P = 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.

Pharmacokinetic-Pharmacodynamic Relationships Describing the Efficacy of Oritavancin in Patients with Staphylococcus aureus Bacteremia

ABSTRACT Bloodstream infections due to antimicrobial-resistant Staphylococcus aureus occur with increasing frequency and represent an important cause of morbidity and mortality. To date, the evaluation of pharmacokinetic-pharmacodynamic relationships for efficacy among patients with bacteremia has been limited. The objectives of these analyses were to evaluate relationships between microbiological and clinical responses for patients with S. aureus bacteremia and exposures for oritavancin, a novel bactericidal glycopeptide in development. Bayesian oritavancin exposure predictions, following treatment with 5, 6.5, 8, or 10 mg/kg of body weight/day, were derived using a validated population pharmacokinetic model for 55 patients with S. aureus bacteremia. Using classification and regression tree analysis, a breakpoint of the percentage of the dosing interval duration for which free-drug concentrations were above the MIC (free-drug % time > MIC) of 22% was identified for microbiological response; the probabilities of success greater than or equal to and less than this value were 93% and 76%, respectively. Using logistic regression, a relationship was found between microbiological response and free-drug % time > MIC (odds ratio = 4.42, P = 0.09, and odds ratio = 8.84, P = 0.05, when one patient, a medical outlier, was excluded). A similar relationship was found for clinical response. These results will be valuable in supporting dose selection of oritavancin for patients with S. aureus bacteremia.

Application of patient population-derived pharmacokinetic-pharmacodynamic relationships to tigecycline breakpoint determination for staphylococci and streptococci.

Correctly determined susceptibility breakpoints are important to both the individual patient and to society at large. A previously derived patient population pharmacokinetic model and Monte Carlo simulation (9999 patients) were used to create a likelihood distribution of tigecycline exposure, as measured by the area under the concentration-time curve at 24 h (AUC(24)). Each resultant AUC(24) value was paired with a clinically relevant fixed MIC value ranging from 0.12 to 2 mg/L. For each AUC(24)-MIC pair, the probability of microbiologic response was calculated using an exposure-response relationship, which was derived from patients with complicated skin and skin structure infections that involved Staphylococcus aureus or streptococci or both. The median probability of microbiologic success was 94% or greater for MIC values up to and including 0.25 mg/L. The median probability of microbiologic success was 66% or less for MIC values of 0.5 mg/L or greater. These data support a susceptibility breakpoint of 0.25 mg/L for S. aureus and streptococci.

Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints

Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration-time curve for 24 h (AUC(SS(0-24))) values for 9999 patients was generated. AUC(SS(0-24)) values were divided by clinically relevant fixed MIC values to derive AUC(SS(0-24))/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach). For the 2nd approach, the probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment was calculated as the proportion of patients with AUC(SS(0-24))/MIC ratios greater than the threshold value of 6.96, the PK-PD target associated with optimal clinical response. Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L. For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.

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.

Exposure–response analyses of tigecycline tolerability in healthy subjects☆

Tigecycline exposure (area under the concentration-time curve [AUC((0-infinity))] and maximum serum concentration [C(max)]) and first occurrence of nausea and vomiting were evaluated in 136 healthy subjects after 12.5- to 300-mg single doses. Nausea was more frequent in females (46%, 10/22) compared with males (31%, 11/36) after 100-mg doses. Most nausea (vomiting) events occurred < or =4 h (<6 h) after tigecycline. For doses < or =100 mg, the median duration of nausea and vomiting was approximately 5 h. Based on logistic regression, increased exposure (AUC((0-infinity)) >C(max)) to tigecycline results in an increased rate of nausea (P < or = .0001; = .0022) and vomiting (P < or = .0001; = .0006). At the median AUC((0-infinity)) (C(max)) for the 50-mg dose group, the probability of nausea and vomiting was 0.26 (0.29) and 0.07 (0.11), respectively. Model-predicted rates of nausea and vomiting were comparable with those observed for the tetracycline class of antibiotics, with tolerable rates predicted after 50-mg doses of tigecycline.

Pharmacokinetics of Tedizolid in Obese and Nonobese Subjects

Obesity, defined as body mass index (BMI) 30 kg/m2, is a growing problem worldwide; the prevalence is 38% in the US adult population.1 Obesity is a risk factor for infection and is associated with antimicrobial treatment failure2 and worse clinical outcomes.3 Communityacquired pneumonia and skin and soft-tissue infections are themost common indications for prescribing outpatient antibiotics for obese patients.4 Obesity can affect the ability of antimicrobial agents to attain therapeutic levels.5,6 Changes in clearance and volume of distribution that may occur in obese patients can alter the dose– exposure relationship with some drugs, resulting in the need to adjust the dose in this patient population.7 With the emergence of antibiotic resistance, dosing decisions become increasingly important. Tedizolid phosphate, the prodrug of the novel oxazolidinone tedizolid, has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in a number of countries, among them the United States and countries in the European Union.8,9 Tedizolid phosphate is rapidly and extensively converted by endogenous phosphatases to its microbiologically active moiety, tedizolid, after administration.10,11 Tedizolid is generally at least 4-fold more potent in vitro than linezolid, the only other currently marketed oxazolidinone antibacterial, against staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci, and enterococci (including vancomycinresistant strains).10,12,13 In 2 recent phase 3 trials in patients with ABSSSIs, tedizolid (200 mg once daily for 6 days) demonstrated noninferior efficacy to linezolid (600 mg twice daily for 10 days) and was generally well tolerated.14,15 The pharmacokinetics (PK) of tedizolid allow for once-daily administration, either orally or intravenously, at equivalent doses.11 Available data suggest that systemic exposure to linezolid is lower in obese than in nonobese patients, which suggests that body weight and/or BMI may be important factors.16–18 The reason for this difference remains undetermined, as does whether linezolid dose modification is warranted for obese patients. In studies of tedizolid, exposure in elderly adults, adolescents, and subjects with severe hepatic or renal impairment (including those requiring hemodialysis) was similar to that in control groups following administration of oral or intravenous tedizolid 200 mg.19,20 The PK in obese subjects were not explicitly studied during the development of tedizolid, but approximately 28% of subjects in phase 1 studies were obese. Thus, a retrospective comparison of the extensive PK data obtained in obese and nonobese subjects would provide useful knowledge of tedizolid PK in obese patients, which could assist in dosing; this is the basis for the current investigation.

Efficacy, safety, tolerability and population pharmacokinetics of tedizolid, a novel antibiotic, in Latino patients with acute bacterial skin and skin structure infections

Acute bacterial skin and skin structure infections are caused mainly by Gram-positive bacteria which are often treated with intravenous vancomycin, daptomycin, or linezolid, with potential step down to oral linezolid for outpatients. Tedizolid phosphate 200mg once daily treatment for six days demonstrated non-inferior efficacy, with a favourable safety profile, compared with linezolid 600mg twice daily treatment for 10 days in the Phase 3 ESTABLISH-1 and -2 trials. The objective of the current post-hoc analysis of the integrated dataset of ESTABLISH-1 and -2 was to evaluate the efficacy and safety of tedizolid (N=182) vs linezolid (N=171) in patients of Latino origin enrolled into these trials. The baseline demographic characteristics of Latino patients were similar between the two treatment groups. Tedizolid demonstrated comparable efficacy to linezolid at 48-72h in the intent-to-treat population (tedizolid: 80.2% vs linezolid: 81.9%). Sustained clinical success rates were comparable between tedizolid- and linezolid-treated Latino patients at end-of-therapy (tedizolid: 86.8% vs linezolid: 88.9%). Tedizolid phosphate treatment was well tolerated by Latino patients in the safety population with lower abnormal platelet counts at end-of-therapy (tedizolid: 3.4% vs linezolid: 11.3%, p=0.0120) and lower incidence of gastrointestinal adverse events (tedizolid: 16.5% vs linezolid: 23.5%). Population pharmacokinetic analysis suggested that estimated tedizolid exposure measures in Latino patients vs non-Latino patients were similar. These findings demonstrate that tedizolid phosphate 200mg, once daily treatment for six days was efficacious and well tolerated by patients of Latino origin, without warranting dose adjustment.

Population Pharmacokinetics and Exposure - Safety Analyses of Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

Nivolumab, a fully human immunoglobulin G4 monoclonal anti‐programmed death‐1 antibody, has demonstrated clinical benefits in multiple tumors, including classical Hodgkin lymphoma. The aim of this study was to characterize the pharmacokinetics (PK) of nivolumab in patients with classical Hodgkin lymphoma using a population approach and to assess the exposure‐response (E‐R) relationship for safety, thereby supporting the dose recommendation in patients with classical Hodgkin lymphoma. Nivolumab PK and the effect of covariates were consistent with that observed in solid tumors, except that baseline clearance of nivolumab was lower in patients with classical Hodgkin lymphoma by 28%. The E‐R analysis for safety, characterized by a Cox proportional hazards model, indicated that the resulting increased nivolumab exposure (average concentration after the first dose) was not a significant predictor of the risk of grade ≥3 drug‐related adverse events. Given the acceptable safety profile and observed benefit (65% objective response rate) with the nivolumab 3 mg/kg every 2 week dosing regimen for classical Hodgkin lymphoma, together with the flat E‐R safety relationship, nivolumab demonstrated a favorable benefit‐risk profile across the range of exposures of 3 mg/kg every 2 weeks in patients with classical Hodgkin lymphoma. Additional model‐based simulation suggested that a flat dose of 240 mg every 2 weeks was predicted to produce similar exposures to that of 3 mg/kg every 2 weeks. Therefore, nivolumab 240 mg every 2 weeks is the recommended dosing regimen in the classical Hodgkin lymphoma population.