Population Pharmacokinetic Modeling and Probability of Target Attainment Analyses in Asian Patients With Community‐Acquired Pneumonia Treated With Ceftaroline Fosamil

Abstract

Efficacy of ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, was demonstrated in a phase 3 study of hospitalized Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III–IV community‐acquired pneumonia (NCT01371838). The objectives of the current analysis were to expand an existing ceftaroline and ceftaroline fosamil population pharmacokinetic (PK) model with data from this phase 3 study and a phase 1 study (NCT01458743) assessing ceftaroline PK in healthy Chinese volunteers and to evaluate the probability of PK/pharmacodynamic (PK/PD) target attainment (PTA) in Asian patients with community‐acquired pneumonia (CAP) treated with ceftaroline fosamil. The ceftaroline plasma concentration‐time course was simulated for 5000 Asian patients with CAP for different renal function subgroups using the final model. PTA was calculated for Streptococcus pneumoniae, Staphylococcus aureus, and non‐extended‐spectrum β‐lactamase‐producing Enterobacteriaceae. PTA was also evaluated for ceftaroline MIC90 values of isolates collected from Asia‐Pacific surveillance studies (2012–2014) and for EUCAST and FDA/CLSI ceftaroline susceptibility break points. The final model reasonably described the ceftaroline PK. Race was not found to be a significant covariate impacting ceftaroline PK, suggesting similar ceftaroline PK in Asian and Western populations when corrected for body weight. High PTAs (90%–100%) were predicted for Asian patients with CAP treated with ceftaroline fosamil, covering MIC90 values of target CAP pathogens from the region. Similarly, >90% PTAs were predicted at EUCAST and FDA/CLSI clinical break points for these pathogens. These results support the use of the ceftaroline fosamil dosing regimens approved in Europe and the United States in Asian patients with PORT III–IV CAP.

Seftarolin, Antibiotik Baru dengan Aktivitas Anti-MRSA: Sebuah Kajian Efektivitas, Keamanan, dan Biaya Penggunaan

“…: Area under the curve C max /MIC : Rasio antara konsentrasi antibiotik maksimum dibandingkan dengan nilai MIC AUC 0-24 /MIC : Rasio antara area dibawah kurva konsentrasi antibiotik persatuan waktu selama interval waktu tertentu dibandingkan dengan nilai MIC %T >MIC : Persentase waktu dalam suatu interval dosis pemberian dimana konsentrasi antibiotik berada di atas nilai MIC Sebagai antibiotik yang bersifat time-dependent, PK-PD indeks yang berkaitan dengan keberhasilan terapi seftarolin adalah %fT >MIC (Bhavnani et al, 2013;Das et al, 2019;Li et al, 2019). Huruf "f" mengindikasikan nilai PK-PD indeks ditentukan dengan mempertimbang-kan pengukuran kadar seftarolin bebas (atau tidak terikat) saja.…”

“…Huruf "f" mengindikasikan nilai PK-PD indeks ditentukan dengan mempertimbang-kan pengukuran kadar seftarolin bebas (atau tidak terikat) saja. Berdasarkan uji pre-klinis, nilai %fT >MIC seftarolin untuk menghasilkan efek statis, 1 log 10 kill, 2 log 10 kill terhadap S. aureus adalah 27%, 31%, dan 35%, secara berturut-turut (Das et al, 2019;Li et al, 2019). Target nilai PK-PD seftarolin untuk menghasilkan efek serupa terhadap beberapa bakteri yang lain dapat dilihat pada tabel 2 (Li et al, 2019).…”

“…Berdasarkan uji pre-klinis, nilai %fT >MIC seftarolin untuk menghasilkan efek statis, 1 log 10 kill, 2 log 10 kill terhadap S. aureus adalah 27%, 31%, dan 35%, secara berturut-turut (Das et al, 2019;Li et al, 2019). Target nilai PK-PD seftarolin untuk menghasilkan efek serupa terhadap beberapa bakteri yang lain dapat dilihat pada tabel 2 (Li et al, 2019). Penelitian uji klinis menunjukkan nilai target %fT >MIC seftarolin yang berbeda dengan hasil uji pre-klinis.…”

The use of extrapolation based on modeling and simulation to support high‐dose regimens of ceftaroline fosamil in pediatric patients with complicated skin and soft‐tissue infections

“…[4][5][6] Elimination is predominantly renal, necessitating dose adjustments for patients with moderate or severe renal impairment. [7][8][9] Renal function, age and presence of acute infection (cSSTI or community-acquired pneumonia [CAP]) have been shown to affect clearance, and presence of infection also affects distribution. 8,9 Common adverse effects of ceftaroline fosamil are typical of the cephalosporin class and include gastrointestinal, immunological and administration site disorders.…”

“…[7][8][9] Renal function, age and presence of acute infection (cSSTI or community-acquired pneumonia [CAP]) have been shown to affect clearance, and presence of infection also affects distribution. 8,9 Common adverse effects of ceftaroline fosamil are typical of the cephalosporin class and include gastrointestinal, immunological and administration site disorders. As a β-lactam, ceftaroline has a wide therapeutic index, with the kidney being the primary organ of toxicity in preclinical studies.…”