Clinical benefits of a Bayesian model for plasma-derived factor VIII/VWF after one year of pharmacokinetic-guided prophylaxis in severe/moderate hemophilia A patients.

INTRODUCTION: Individual pharmacokinetic (PK) profiling in hemophilia A (HA) helps to individualize prophylaxis using population PK models (popPK). A specific popPK model for plasma-derived factor VIII containing von-Willebrand Factor (pdFVIII/VWF) was developed. AIM: To compare standard versus PK-driven prophylaxis, using a generic or a specific popPK model for pdFVIII/VWF. MATERIALS AND METHODS: A prospective study conducted in HA patients in prophylaxis with pdFVIII/VWF (Fanhdi®) comparing three one-year study periods: (1) standard prophylaxis, (2) PK-guided prophylaxis using a generic pdFVIII popPK model which described FVIII activity irrespective of FVIII concentrate, and (3) PK-guided prophylaxis with specific pdFVIII/VWF popPK model. PK parameters analyzed were half-life, trough levels (TL) at 24, 48 and 72 h, and time to reach FVIII levels of 1, 2, 5% (T5%). Clinical outcomes were dose/kg, FVIII consumption, annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), spontaneous and traumatic bleeds. RESULTS: Of the 30 analyzed patients, 28 had severe HA and the median age was 31.2. Fifteen patient's prophylaxis doses were PK-adjusted. After the generic PK-guided prophylaxis period, younger patients showed more joint bleeds, a shorter half-life, and lower TL48, TL72 and T5%. Using the specific pdFVIII/VWF popPK model compared with standard prophylaxis, a lower spontaneous AJBR was observed in the entire cohort and in patients aged >15 years. Additionally, lower spontaneous ABR was reported in patients aged ≤15 years comparing specific and generic models. CONCLUSIONS: PK-guided prophylaxis with a specific pdFVIII/VWF popPK model allowed treatment individualization and improved bleeding control in routine clinical practice, especially in younger patients with short pdFVIII/VWF half-lives.

Ceftolozane/Tazobactam Dosing Requirements Against Pseudomonas aeruginosa Bacteremia.

OBJECTIVES: To assess the probability of reaching adequate pharmacokinetic/pharmacodynamics values for ceftolozane/tazobactam at different doses and degrees of renal functions in patients with Pseudomonas aeruginosa bacteremia. METHODS: Six dosing regimens were evaluated: 0.5/0.25 g, 1/0.5 g, and 2/1 g every 8 hours given as 1 hour or 3 hours infusions. Pharmacokinetic data were obtained from the literature. Susceptibility data to ceftolozane were collected from patients with P aeruginosa infection treated with ceftolozane-tazobactam. Probability of reaching a fraction of time (fT) >40% minimum inhibitory concentration (MIC) and fT >100%MIC value for ceftolozane at 3 different renal clearance values was evaluated. For tazobactam, the probability of reaching an fT >40% and >70% for 3 limit values was calculated. RESULTS: Thirty-seven strains were included. For ceftolozane, the probability of reaching a fT >40%MIC was greater than 90% for any degree of renal function. The probability of reaching a fT >100%MIC for 1 g dose infused over 1 hour and 3 hours was 82.2% and 86.4% for a creatinine clearance (ClCr) >90 mL/min. Using a 2 g dose, the probability was greater than 90% for both infusions rates. For tazobactam, the probability of reaching a value of fT >50% of the limit concentrations was greater than 90% for a ClCr of 70 mL/min. In the case of a ClCr >90 mL/min and limit concentration values ≥ 0.25 mg/mL, only extended infusions showed a probability >90%. CONCLUSIONS AND RELEVANCE: The standard doses of ceftolozane/tazobactam achieve an adequate fT >40%MIC value. However, doses of 2 g in extended infusion is necessary to reach a value of fT >100%MIC, especially in patients with an increased renal clearance and high levels of beta-lactamases expression.