Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis

Bulitta, Jürgen B.; Jiao, Yuanyuan; Drescher, Stefanie K.; Oliver, Antonio; Louie, Arnold; Moyá, Bartolomé; Tao, Xun; Wittau, Mathias; Tsuji, Brian T.; Zavascki, Alexandre Prehn; Shin, Beom Soo; Drusano, George L.; Sörgel, Fritz; Landersdorfer, Cornelia B.

doi:10.1007/s40262-018-0678-x

Cited by 15 publications

(30 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, obese volunteers had a higher V c (6.4 liters), and adjusted body weight produced a better covariate model fit than TBW (23). These results are unsurprising because, due to modern improvements in CF treatment, these patients tend to more closely resemble the general population than admitted CF patients did a few decades ago (26).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Kidd

Sakon

Oleksiuk

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg−1; CLNR, 0.59 ± 0.30 liters · h−1; CLθ, 5.97 × 10−3 ± 1.24 × 10−3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h−1. The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter−1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Kidd

Sakon

Oleksiuk

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…While β-lactams are relatively hydrophilic molecules [39,40] with a protein binding of 40% or less in human plasma for many compounds, several β-lactams, especially those with Gram-positive activity, display a higher protein binding [3,5,6,16,41,42,43]. These more highly bound β-lactams include dicloxacillin, cloxacillin, methicillin, ticarcillin and aztreonam of which PK has been compared between patients with CF and healthy volunteers [5,6,9,44,45,46].…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacokinetics (PK) of patients with cystic fibrosis (CF) has been reported to considerably differ from that in healthy volunteers since the 1970s [1,2,3,4]. This was especially true for early studies in patients with CF for β-lactams with high protein binding (such as dicloxacillin and cloxacillin) [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…These studies employed population PK modeling to account for the differences in body size and body composition via allometric scaling based on lean body mass (LBM). This approach explained most of the differences in clearance and volume of distribution between both subject groups [3]. However, for aztreonam, the most highly bound β-lactam in these newer studies [9], the unbound fraction in serum was approximately 19% higher in patients with CF compared to that in healthy volunteers.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding

et al. 2019

Self Cite

View full text Add to dashboard Cite

The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.

show abstract

“…CF patients generally require larger loading doses of antibiotics compared to the general population [1]. Some suspect this is due to lower protein binding and alterations in the volume of distribution due to chronic malnutrition [86]. Two commonly classes of antibiotics prescribed during a PEx, antipseudomonal beta-lactams and aminoglycosides, have interesting pharmacokinetic implications [74].…”

Section: Pharmacokinetic Considerationsmentioning

confidence: 99%