Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P < .001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection.

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended.

Current dosing practices for perioperative factor VIII concentrate treatment in mild haemophilia A patients result in FVIII levels above target.

BACKGROUND: In patients with haemophilia A (HA) perioperative dosing of factor VIII (FVIII) concentrate is based on body weight, historical FVIII level, in vivo recovery and FVIII level target values. In moderate and severe HA patients, this dosing regimen frequently leads to perioperative FVIII levels below and above target. This has not yet been evaluated in mild HA patients. OBJECTIVES: To evaluate perioperative FVIII concentrate treatment in mild HA patients and to assess the frequency of FVIII levels below or above target. PATIENTS/METHODS: This retrospective single-centre study collected data from medical files of mild HA patients undergoing surgery and treated with FVIII concentrate. FVIII levels were compared to their target ranges and predictive factors for levels outside the target ranges were determined by logistic regression. RESULTS: Fifty surgeries performed in 34 patients were evaluated. Median age was 47 years and median historical FVIII level was 0.14 IU/mL. Preoperative peak FVIII level was above or below the target range in 80% and 6.7% of surgeries, respectively. Postoperatively, the percentages above and below target trough ranges were 55.8% and 12.8%. Patients with blood group 0 had the highest risk on the preoperative peak FVIII level being above target. In addition, patients who had a preoperative baseline FVIII level of >0.10 IU/mL higher than their historical FVIII level had a higher preoperative peak FVIII level than patients without this increase. CONCLUSIONS: Dosing above FVIII target ranges with FVIII concentrates occurs frequently during perioperative treatment of mild HA patients. These results underline the necessity for better patient-tailored treatment.

Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study.

INTRODUCTION: Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption. METHODS AND ANALYSIS: In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment. ETHICS AND DISSEMINATION: The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences. TRIAL REGISTRATION NUMBER: NTR5383; Pre-results.

Paracetamol clinical dosing routine leads to paracetamol underexposure in an adult severely ill sub-Saharan African hospital population: a drug concentration measurement study.

BACKGROUND: Hospitals in sub-Saharan Africa (SSA) continue to receive high numbers of severely ill (HIV-infected) patients with physical pain that may suffer from hepatic and renal dysfunction. Paracetamol is widely used for pain relief in this setting but it is unknown whether therapeutic drug concentrations are attained. The aim of this study was to assess the occurrence of therapeutic, sub-therapeutic and toxic paracetamol concentrations in SSA adult hospital population. METHODS: In a cross-sectional study, plasma paracetamol concentrations were measured in patients with an oral prescription in a referral hospital in Mozambique. From August to November 2015, a maximum of four blood samples were drawn on different time points for paracetamol concentration measurement and biochemical analysis. Study endpoints were the percentage of participants with therapeutic (≥ 10 and ≤ 20 mg/L), sub-therapeutic (< 10 mg/L) and toxic (> 75 mg/L) concentrations. RESULTS: Seventy-six patients with a median age of 37 years, a body mass index of 18.2, a haemoglobin concentration of 10.3 g/dL and an albumin of 29 g/L yielded 225 samples. 13.4% of participants had one or more therapeutic paracetamol concentrations. 86.6% had a sub-therapeutic concentration at all time points and 70.2% had two or more concentrations below the lower limit of quantification. No potentially toxic concentrations were found. CONCLUSIONS: Routine oral dosing practices in a SSA hospital resulted in substantial underexposure to paracetamol. Palliation is likely to be sub-standard and oral palliative drug pharmacokinetics and dispensing procedures in this setting need further investigation.

Pharmacokinetics of Antibiotics in Sub-Saharan African Patient Populations: A Systematic Review.

BACKGROUND: In sub-Saharan Africa (SSA), severe febrile illness accounts for a large majority of medical admissions. SSA patients may also suffer from cachexia and organ dysfunction resulting from tuberculosis, hepatitis B, and hypertension. It is hard to tell how these conditions influence the pharmacokinetics (PK) of antibiotics in this population. The aim of this systematic review was to summarize antibiotic PK data of SSA adult patient populations to clarify whether inappropriate drug concentrations that may also lead to antimicrobial resistance are likely to occur. METHODS: An electronic search was conducted in Ovid MEDLINE, Embase, and the African Index Medicus collecting studies from 1946 to May 2016. Reviewers independently selected studies reporting outcome data on volume of distribution (V), clearance, and half-life. Relevant information was abstracted and quality assessed. RESULTS: Twelve studies were selected, addressing 6 antibiotic classes. There were 6 studies on fluoroquinolones and 1 on ß-lactam antibiotics. Nine out of 12 originated from South Africa and 6 of those dealt with intensive care unit (ICU) populations. The quality of most studies was low. Studies on amikacin, teicoplanin, and ertapenem (n = 4) displayed a pattern of a large V with low drug concentrations. Fluoroquinolone PK changes were less prominent and more diverse whereas the probability of pharmacodynamic target attainment was low for the treatment of tuberculosis in South Africa. Interindividual variability of V was high for 10/12 studies. CONCLUSIONS: Antibiotic PK data of SSA adult patient populations are scarce, but disease-induced inappropriate drug concentrations do occur. Data from non-ICU, severely ill patients, and ß-lactam data are particularly lacking, whereas ß-lactam antibiotics are commonly used, and typically vulnerable to disease-induced PK changes. Studies investigating the PK and pharmacodynamics of ß-lactam antibiotics in severely ill, adult SSA patient populations are needed to improve local antibiotic dosing strategies.

Differences in clearance of mycophenolic acid among renal transplant recipients, hematopoietic stem cell transplant recipients, and patients with autoimmune disease.

For more than a decade, mycophenolate mofetil (MMF) has been used as an immunosuppressive drug in solid organ transplant recipients to prevent graft rejection. After oral administration, the prodrug MMF is rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA). MMF is being used increasingly in hematopoietic stem cell transplantation (HSCTx) and autoimmune diseases (AID). The pharmacokinetics of MPA are markedly different in these patients. In comparison with renal transplant recipients (RTx), MPA clearance is increased in HSCTx patients and decreased in AIDS. The aim of this study was to characterize MPA clearance in RTx, HSCTx, and AID patients and to test whether the differences in clearance can be described by clinical chemical parameters. MPA concentration-time profiles from 19 RTx patients coprescribed cyclosporine, 17 RTx patients coprescribed tacrolimus, 38 HSCTx patients coprescribed cyclosporine, and 36 patients with AID were analyzed retrospectively with nonlinear mixed effects modeling (first-order conditional estimate). The following covariates were tested: indication for MMF treatment, sex, age, weight, plasma albumin, cyclosporine cotreatment, dose and predose blood concentration, creatinine clearance, and hemoglobin. Pharmacokinetics of MPA were described by a two-compartment model with time-lagged first-order absorption. MPA clearance was correlated in univariate analysis with plasma albumin, cyclosporine dose and predose blood concentration, creatinine clearance, hemoglobin, and indication for MMF treatment (RTx, HSCTx, or AID) (P < 0.001). All significant covariates were combined in an intermediate multivariate model followed by backward elimination. The indication for MMF treatment could be removed from the intermediate model without compromising the fit. The correlation between clearance and cyclosporine predose concentrations and plasma albumin remained significant in the final model and could describe the difference in clearance between the different indications for MMF treatment. Median clearance was 30.2, 45.6, and 10.7 L/h in RTx, HSCTx, and AID patients, respectively. In conclusion, plasma albumin concentrations and cyclosporine predose concentrations are able to describe the difference in MPA clearance among RTx, HSCTx, and AID patients.

Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed at analyzing the pharmacokinetics of MMF in a population of HCT recipients representative for everyday practice. From 15 HCT recipients, serial plasma samples were taken after twice-daily oral intake of MMF. Plasma concentrations of total MPA and its glucuronide metabolites, as well as free MPA, were quantified. Median apparent oral MPA clearance (CL/F), apparent half-life, and total MPA area under the curve for hours 0 to 12 (AUC0-12, normalized to 1000 mg MMF) were, respectively, 56 L/h (range: 29-98 L/h), 2.3 hours (range: 0.8-5.7 hours), and 18.0 mg*h/L (range: 10-35 mg*h/L). Total MPA concentrations were below 2 mg/L 8 hours after MMF administration, indicating reduced enterohepatic recirculation. Median free MPA AUC0-12 (normalized to 1000 mg MMF) was 224 microg*h/L (range: 56-411 microg*h/L). Because of high CL/F, total MPA exposure in HCT recipients is low and apparent half-life is short in comparison with reference values from renal transplantation. Exposure may be improved in HCT recipients by higher or more frequent MMF dosing.

Therapeutic drug monitoring of mycophenolic acid: does it improve patient outcome?

Treatment with the immunosuppressive agent mycophenolate mofetil (MMF) decreases the risk of rejection after renal transplantation and improves graft survival compared with azathioprine. The exposure to the active metabolite mycophenolic acid (MPA) is correlated to the risk of developing acute rejection. The interpatient variability in exposure of MPA is wide relative to the proposed therapeutic window of the MPA AUC(0 12) (30 - 60 mg.h/l). The pharmacokinetics of MPA are influenced by patient characteristics such as gender, time after transplantation, serum albumin concentration, renal function, comedication and pharmacogenetic factors. Therapeutic drug monitoring is likely to reduce inter-patient variability. Limited sampling strategies are used to predict the full AUC(0 12). Three prospective randomised studies compared concentration controlled MMF therapy to a fixed-dose regimen. Preliminary outcomes of these studies showed conflicting results and longer follow up is needed to further clarify the role of therapeutic drug monitoring in increasing the therapeutic potential of MMF.