A Minimal PBPK Model for Plasma and Cerebrospinal Fluid Pharmacokinetics of Trastuzumab after Intracerebroventricular Administration in Patients with HER2-Positive Brain Metastatic Localizations.

BACKGROUND: Dosing regimens of trastuzumab administered by intracerebroventricular (icv) route to patients with HER2-positive brain localizations remain empirical. The objectives of this study were to describe pharmacokinetics (PK) of trastuzumab in human plasma and cerebrospinal fluid (CSF) after simultaneous icv and intravenous (iv) administration using a minimal physiologically-based pharmacokinetic model (mPBPK) and to perform simulations of alternative dosing regimens to achieve therapeutic concentrations in CSF. METHODS: Plasma and CSF PK data were collected in two patients with HER2-positive brain localizations. A mPBPK model for mAbs consisting of four compartments (tight and leaky tissues, plasma and lymph) was enriched by an additional compartment for ventricular CSF. The comparison between observed and model-predicted concentrations was evaluated using prediction error (PE). RESULTS: The developed mPBPK model described plasma and CSF trastuzumab concentrations reasonably well with mean PE for plasma and CSF data of 41.8% [interquartile range, IQR = -9.48; 40.6] and 18.3% [-36.7; 60.6], respectively, for patient 1 and 11.4% [-10.8; 28.7] and 22.5% [-27.7; 77.9], respectively, for patient 2. Trastuzumab showed fast clearance from CSF to plasma with Cmin,ss of 0.56 and 0.85 mg/L for 100 and 150 mg q1wk, respectively. Repeated dosing of 100 and 150 mg q3day resulted in Cmin,ss of 10.3 and 15.4 mg/L, respectively. Trastuzumab CSF target concentrations are achieved rapidly and maintained above 60 mg/L from 7 days after a continuous perfusion at 1.0 mg/h. CONCLUSION: Continuous icv infusion of trastuzumab at 1.0 mg/h could be an alternative dosing regimen to rapidly achieve intraventricular CSF therapeutic concentrations.

Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma.

The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.

Iloprost Use in Patients with Persistent Intestinal Ischemia Unsuitable for Revascularization.

BACKGROUND: Persistent or chronic intestinal ischemic injury (i3) can lead to severe malnutrition and acute mesenteric ischemia. Although recommended, revascularization of splanchnic arteries is sometimes unrealizable. METHODS: We report a case series of iloprost use in consecutive stable patients with persistent i3 unsuitable for revascularization followed in a tertiary care center. The feasibility of revascularization was discussed and ruled out by a multidisciplinary team, and informed consent was obtained prior to consideration of a vasoactive therapy. Therapeutic response was defined at 6 months by a decrease in the use of analgesic and parenteral nutrition, and no need for intestinal resection. RESULTS: Between 2006 and 2015, 6 patients (mean age: 51) were included. Splanchnic vascular insufficiency was due to superior mesenteric artery (SMA) thrombosis (n = 4), dissection of the celiac trunk and SMA (n = 1), or repeated vasospasm resulting in chronic nonocclusive mesenteric ischemia (n = 1). Iloprost was delivered via continuous intravenous perfusion at a maximum dosage of 2 ng/kg/min for 6 hours/day on 4 consecutive days, without severe adverse events. Therapeutic response was observed in 4 patients, 3 of which completely stopped parenteral nutrition and analgesic with no need for intestinal resection. CONCLUSIONS: Our results are consistent with findings of a favorable effect of iloprost in patients with persistent splanchnic ischemia that should be confirmed in prospective trials.

Once-daily prolonged release tacrolimus in liver transplantation: Experts' literature review and recommendations.

The efficacy and safety of tacrolimus (Tac) twice daily (bid) and once a day (qd) formulations are considered to be similar. However, the available information regarding initiation of Tac qd is sparse, and practical information is lacking. On the basis of a literature review, clinical efficacy, and safety trials, French experts in the liver transplantation field were asked to highlight pharmacokinetic (PK) differences between both formulations to assess efficacy and safety of the qd formulation in the context of de novo initiation or conversion and to provide their recommendations for initiation and day-to-day management of Tac qd. The same efficacy and safety profile is found for both immediate-release and prolonged-release Tac. PK differences carry on absorption because of the difference in formulations but not on metabolism or excretion. Tac qd offers a better reproducibility in exposure than Tac bid but is associated with an increased risk of disturbed absorption in case of a change in intestinal motility. The same therapeutic drug monitoring with Tac qd and bid could be applied, based on minimal concentration (trough level; C(min)), as there is a similar strong correlation between C(min) and the area under the curve (AUC) for both formulations. Different protocols for Tac qd initiation were described through numerous studies, except for early conversion: initiation on day 0, using 0.10 to 0.20 mg/kg/day as monotherapy, or lower dosages in case of concomitant immunosuppressant treatment or poor graft quality; early conversion from day 5 to 6 months, preferably before hospital discharge, using a 1 to 1.3 mg/kg/day schedule and with first C(min) assessment 48 hours after the conversion; and later conversion (>6 months posttransplantation) using a milligram-to-milligram dosage schedule, and with dose adjustment based on weekly C(min) measurement. Experts underline that an increase in treatment adherence was expected using Tac qd in liver recipients. In conclusion, Tac qd has the same efficacy and safety profile as Tac bid. De novo introduction or later conversion are well documented but could differ from day-to-day practice.

Determination of the most influential sources of variability in tacrolimus trough blood concentrations in adult liver transplant recipients: a bottom-up approach.

Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (P(fat)), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLi(typ)), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fu(p)), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fu(p), CLi(typ), bioavailability, body weight, hematocrit, CYP3A5 polymorphism, P(fat), and CYP3A4 inhibitory drug-drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient's hematocrit and body weight are proposed.

A randomized study comparing IGL-1 to the University of Wisconsin preservation solution in liver transplantation.

BACKGROUND: Institut Georges Lopez-1 (IGL-1) is a new preservation solution with lower potassium and lower viscosity than University Wisconsin solution (UW). These characteristics which improve liver preservation lead us to evaluate clinical effects of IGL-1 in a randomized controlled study with UW. MATERIAL/METHODS: From June 2007 to July 2009, after exclusion of partial graft, combined transplantation and fulminant hepatic failure, 140 deceased donor allografts were randomly assigned to IGL-1 (n=48) or UW (n=92) solution. Variables concerning donors and recipients were collected including liver tests (total serum bilirubin, prothrombin time and transaminases) were analyzed until postoperative day 30. Incidences of hepatic artery thrombosis (HAT), primary non function (PNF) and biliary non anastomotic strictures (NAS) were analyzed. The comparative analysis of costs was realized. RESULTS: Donor and recipients characteristics were similar in both groups. Volume of preservation solution utilized for harvesting was identical. Duration of cold ischemia (472±142 vs. 477±122 min), surgery (427±97 vs. 437±94 min) and proportion of extended criteria donor was similar. Postoperative kinetic and level liver tests were similar. Rate of PNF (2% vs. 4%), early retransplantation (6% vs. 7%), incidence of biliary NAS (2% vs. 3%) and HAT (6% vs. 4%) were similar. Mean intensive care unit (ICU) stay was similar (5.6 vs. 6.1 days). However costs related to preservation solution for one liver procurement were 992.0 for IGL-1 vs. 1609.0 Euros for UW. CONCLUSIONS: Results of this randomized study shows that the efficacy and safety of IGL-1 are comparable to those of the reference UW with a lower cost.

Pharmacokinetic/pharmacodynamic and time-to-event models of ribavirin-induced anaemia in chronic hepatitis C.

BACKGROUND: Interferon (IFN)-alpha and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C. However, ribavirin induces anaemia, especially by haemolysis, an adverse effect that is dose-limiting. OBJECTIVES: The aim of this study was to determine the relationships between ribavirin exposure and haemoglobin time-course, the time-to-anaemia and the covariates influencing these relationships in a population of patients treated for chronic hepatitis C. In addition, we also intended to establish a simple rule defining the need for dosage adjustment, using data obtained during the first month of treatment. METHODS: A retrospective analysis of 99 patients treated with IFNalpha plus ribavirin, with known dosage administration history, liver biopsy, demographic data, red blood cell counts, haemoglobin level (1037 measurements, median 10 per patient, range 2-31) and serum creatinine during the entire treatment period (178 days, range 53-382 days) was conducted. The data were analysed by a pharmacokinetic/pharmacodynamic population model and Weibull time-to-anaemia model. The rule defining the need for dosage adjustment was as follows: adjustment was needed if haemoglobin at steady state (H(ss)), estimated by the Bayesian method based on data obtained during the first month of treatment, was <12 g/dL for men or <11 g/dL for women. RESULTS: In both models, anaemia was related to the exposure of erythrocytes to ribavirin at time t (RT in mg/kg/day) by a maximum effect model, with RT(50) (dosage administration rate at which half the maximal effect is reached) approximately 12 mg/kg/day, and the significant covariates were initial haemoglobin level and bodyweight. Performances of a Bayesian prediction of H(ss) based on two early haemoglobin level measurements were encouraging (mean prediction error 0.12 g/dL, precision 0.85 g/dL). The proposed rule for the need of dosage adjustment was able to predict the actual evolution of the dosage regimen in 76% of non-adapted patients and 69% of adapted patients. CONCLUSION: The current guidelines for ribavirin dosage administration, based on bodyweight, are adequate, at least in the 45-105 kg range. Results indicate that Bayesian therapeutic monitoring could be helpful in controlling ribavirin-induced anaemia.