Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation.

PURPOSE: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections. METHODS: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection. RESULTS: Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies. CONCLUSION: A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program. CLINICAL TRIAL REGISTRATION: NCT01689207; NCT02655419; NCT03329092; NCT03580044.

Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development.

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).

Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials.

OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.

Comparing probability of target attainment against Staphylococcus aureus for ceftaroline fosamil, vancomycin, daptomycin, linezolid, and ceftriaxone in complicated skin and soft tissue infection using pharmacokinetic/pharmacodynamic models.

For recently licensed antibiotics, such as the cephalosporin ceftaroline fosamil, probability of target attainment (PTA) curves, showing the percentage of patients reaching a predefined pharmacokinetic (PK)/pharmacodynamic (PD) target at different bacterial minimum inhibitory concentrations (MICs), have been used to support and justify dose recommendations across patient populations. However, information on PTA for older antibiotics is limited. A retrospective analysis was conducted to construct PTA curves for 4 antibiotics against Staphylococcus aureus in patients with complicated skin and soft tissue infections (cSSTIs). PK models for vancomycin, linezolid, daptomycin, and ceftriaxone were selected from the literature based on large numbers of subjects with covariates representative of patients in Europe and/or the United States. An existing model was available for ceftaroline fosamil. Standard and high-dosage regimens were used to compare the PTA of each antibiotic at MIC values 0.03 to 64 mg/L for a simulated set of patients with cSSTI caused by S. aureus. These were compared to proportions of S. aureus isolates at each MIC from global surveillance data. Ceftaroline achieved PTAs >99.9% for bacteriostatic and bactericidal targets at the MIC90 (1 mg/L), whereas the comparators failed to achieve PTAs >90%, at bacteriostatic or bactericidal targets, even when clinical doses were increased beyond those recommended. PTA analysis can be used to compare different drugs with the same simulated patient dataset, subject to availability of an appropriate PK model and robust exposure targets. This analysis shows that some antibiotics commonly used to treat cSSTIs may fail to reach high PTAs relative to contemporary MIC90 estimates.

Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups.

Ceftazidime-avibactam is a novel ß-lactam/ß-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).

Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa.

Clinical susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa for the ceftazidime-avibactam dosage regimen of 2,000/500 mg every 8 h (q8h) by 2-h intravenous infusion (adjusted for renal function) have been established by the FDA, CLSI, and EUCAST as susceptible (MIC, ≤8 mg/liter) and resistant (MIC, >8 mg/liter). The key supportive data from pharmacokinetic/pharmacodynamic analyses, in vitro surveillance, including molecular understanding of relevant resistance mechanisms, and efficacy in regulatory clinical trials are collated and analyzed here.

Population Pharmacokinetic Modelling of Ceftazidime and Avibactam in the Plasma and Epithelial Lining Fluid of Healthy Volunteers.

OBJECTIVES: Our objective was to develop population pharmacokinetic (PK) models for ceftazidime and avibactam in the plasma and epithelial lining fluid (ELF) of healthy volunteers and to compare ELF concentrations to plasma PK/pharmacodynamic (PD) targets. METHODS: Plasma and ELF population PK models were developed for ceftazidime and avibactam concentration data from 42 subjects (NCT01395420). Two- and three-compartment plasma PK models were fitted to ceftazidime and avibactam plasma PK data, and different plasma-ELF linked models were evaluated. Using best-fitting models, plasma and ELF concentration-time profiles were simulated for 1000 subjects. ELF concentration-time profiles for ceftazidime/avibactam 2000-500 mg every 8 h were compared with plasma PK/PD targets for ceftazidime (50% of time above [fT >] 8 mg/l) and avibactam (50% fT > 1 mg/l). RESULTS: Three-compartment PK models best fitted the plasma concentration data for ceftazidime and avibactam. ELF data for both drugs were best described by a direct response (instantaneous equilibrium) model. Ceftazidime plasma-ELF relationships were best described by a saturable Michaelis-Menten model. For avibactam, departure from plasma-ELF relationship linearity was more modest than for ceftazidime. ELF:plasma penetration ratios of both ceftazidime (52%) and avibactam (42%) at plasma concentrations relevant for efficacy (~ 8 mg/l for ceftazidime and ~ 1 mg/l for avibactam) were greater than previously calculated using non-compartmental area under the curve (AUC) methods, which average across the entire concentration range. Ceftazidime and avibactam ELF exposures exceeded their respective plasma PK/PD time-above-threshold targets by the dosing interval mid-point in most subjects. CONCLUSIONS: This compartmental modelling analysis suggests ELF exposures of both ceftazidime and avibactam exceed levels required for efficacy in plasma.

Population pharmacokinetics of rosuvastatin in pediatric patients with heterozygous familial hypercholesterolemia.

PURPOSE: Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label [CHARON; NCT01078675] and Study 4522IL/0086) were used to describe rosuvastatin pharmacokinetics in patients with heterozygous familial hypercholesterolemia aged ≥6 to <18 years. METHODS: Rosuvastatin concentration-time data were analyzed via non-linear mixed-effects modeling (NONMEM), with clearance (CL/F) as the pre-defined key pharmacokinetic parameter of interest. In addition, descriptive comparisons between pediatric patients and adults (healthy and dyslipidemic) were performed. The dataset included 214 pediatric patients, with 2,029 rosuvastatin concentrations. RESULTS: A linear two-compartment model with first-order absorption and elimination processes adequately described the combined dataset. Weight and gender were significant covariates for CL/F, with moderate between-patient variability remaining (coefficient of variation (CV) 40 %): CL/F in female children was approximately 30 % lower than in male children, and there was a twofold mean difference in CL/F across the observed weight range. Age was not a significant covariate after accounting for weight and gender differences. However, weight and gender only reduced between-patient variability from 45 (without covariates) to 40 % and are considered unlikely to be clinically relevant. CONCLUSIONS: Rosuvastatin pharmacokinetics appeared generally predictable with respect to dose, and time (study duration) and the exposure (dose-normalized area under the plasma concentration-time curve at steady state (AUCss)) in children and adolescents appeared to be similar or lower than adult patients with dyslipidemia.

The effect of different etiologies of hepatic impairment on the pharmacokinetics of gefitinib.

PURPOSE: We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies. METHODS: In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days. RESULTS: In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts. CONCLUSIONS: We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.

Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2).

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

Development of teicoplanin dosage guidelines for patients treated within an outpatient parenteral antibiotic therapy (OPAT) programme.

OBJECTIVES: The long elimination half-life of teicoplanin facilitates outpatient parenteral antibiotic therapy (OPAT) with thrice-weekly dosing. This study aimed to develop teicoplanin dosage guidelines for OPAT use from routine clinical data. METHODS: Patients received 15-25 mg/kg/day for 3 days, then 15-25 mg/kg thrice weekly. Trough concentrations were measured weekly and doses adjusted to maintain 20-30 or 10-20 mg/L according to clinical condition. Concentration-time data were analysed using the pharmacokinetic package NONMEM and the final model was used to develop new dosage guidelines. RESULTS: Data from 94 and 36 patients were used for model development and validation, respectively. Patient ages ranged from 15 to 94 years, weights from 43 to 146 kg and estimated CL(CR) from 9 to 195 mL/min. Teicoplanin concentrations (n = 670) ranged from 6.7 to 66.9 mg/L and a one-compartment model adequately described the data. The typical estimate of CL was 0.542 L/h and changed by 10.6% for every 10 mL/min difference from a CL(CR) of 66 mL/min. V was 1.62 L/kg. Dosage guidelines based on body weight and CL(CR) can be expected to lead to a significant improvement in the proportion of concentrations in the range 20-30 mg/L. Alternative doses aimed at lower target concentrations have also been developed. CONCLUSIONS: New dosage guidelines have been developed to support thrice-weekly administration of teicoplanin in an OPAT setting.

A phase I study to determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy male volunteers.

OBJECTIVES: To determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy volunteers. METHODS: An open-label, single-center, phase I study in healthy male volunteers. Each volunteer received a single 250 mg oral dose of gefitinib on day 1. On days 11-14, oral loading doses of 60 mg tamoxifen were administered, followed by 20 mg tamoxifen for a further 16 days to maintain steady-state exposure. On day 24, volunteers received a second single 250 mg oral dose of gefitinib. The last dose of tamoxifen was given on day 30. Pharmacokinetic and safety assessments were conducted throughout the trial. RESULTS: A total of 18 volunteers were recruited. The presence of tamoxifen did not have a clinically significant effect on the primary variables AUC and Cmax of gefitinib, nor on the secondary variables AUC(0-t), tmax, t1/2, and lambdaz. The geometric least square mean values for AUC were 3,407.6 versus 3,397.9 ng.h/ml in the absence and presence of tamoxifen, respectively (90% CL 0.894, 1.112) and for Cmax were 110.8 versus 103.6 ng/ml, respectively (90% CL 0.786, 1.111). The combination of gefitinib with tamoxifen was generally well tolerated by the volunteers. There were no serious adverse events and no volunteer discontinued the study due to an adverse event. NCI-CTC grade 1/2 drug-related adverse events were observed in seven volunteers, including loose stools and skin events associated with gefitinib, and lethargy and headache, flushing, and dizziness associated with tamoxifen. CONCLUSIONS: This study suggests that tamoxifen has no significant effect on the pharmacokinetics, tolerability, or safety of a single 250 mg oral dose of gefitinib. Therefore, in clinical investigations of this combination, no dose adjustment of gefitinib is indicated.