Semi-mechanistic Pharmacokinetic/Pharmacodynamic model of three pegylated rHuEPO and ior®EPOCIM in New Zealand rabbits.

Marketed formulations of erythropoietin (EPO) ior®EPOCIM, MIRCERA® and two newly developed pegylated-EPO analogues (PEG-EPO 32 and 40 kDa) formulations were intravenously administered to New Zealand rabbits. A semi-mechanistic Pharmacokinetic/Pharmacodynamic (PK/PD) model describing in a simultaneous and integrated form the time course of reticulocytes, red blood cells and hemoglobin was built to account for the time course of hematopoiesis stimulation after erythropoietin administration. Data analysis was performed based on the population approach with the software NONMEM version 7.3. Erythropoietin disposition of each of the administered formulations was best described with a two compartment model and linear elimination. Different formulations show different clearance and apparent volume of distribution of the central compartment but share estimates of inter-compartmental clearance and apparent peripheral volume of distribution. A semi-mechanistic model including cell proliferation, maturation, and homeostatic regulation provided a good description of the data regardless the type of erythropoietin formulation administered. The system-, and drug-related parameters showed consistency and differed across formulations, respectively. A single IV administration of PEG-EPO 32 and 40 kDa formulations in New Zealand rabbits achieves a median change of 27% and 22% on RET levels, and of 47% and 63% on RBC and HGB levels, respectively compared to MIRCERA®. The administration of new branched PEG-chains formulations improves PK and PD properties of EPO, in terms of increasing elimination half-lives and pharmacological activity on RET, RBC and HGB compared to commercially available formulations (ior®EPOCIM and MIRCERA®).

Commentary on Pharmacometrics for Immunotherapy.

This commentary provides an overview of recent examples of pharmacometrics applied during the clinical development of two antagonists of the programmed death-1 (PD-1) cell surface receptor, pembrolizumab and nivolumab. Despite the remarkable achievements obtained in predicting the correct dosing schedule from different quantitative approaches, data indicated a great degree of heterogeneity in tumor response. To achieve therapeutic goals the search for predictive biomarkers associated with a lack of response and mechanism-based combination studies are warranted.

Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome.

INTRODUCTION: The relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship. METHODS: Low capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at 3 months postoperatively. Rate of learning (AL) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat's TFC result at postoperative day (POD) 7 was correlated with its AL and PT from the MWM data sets at postoperative day POD 90. RESULTS: A single exponential decay model best described AL in the MWM with LCR and surgery (LCR-SURG) being the only significant covariates; first order AL rate constant was 0.07 s(-1) in LCR-SURG and 0.16s(-1) in the remaining groups (p<0.05). TFC was significantly correlated with both AL (R=0.74; p<0.0001) and PT (R=0.49; p<0.01). CONCLUSION: Severity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory.

Optimizing oncology therapeutics through quantitative translational and clinical pharmacology: challenges and opportunities.

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.

Modeling the effect of propofol and remifentanil combinations for sedation-analgesia in endoscopic procedures using an Adaptive Neuro Fuzzy Inference System (ANFIS).

BACKGROUND: The increasing demand for anesthetic procedures in the gastrointestinal endoscopy area has not been followed by a similar increase in the methods to provide and control sedation and analgesia for these patients. In this study, we evaluated different combinations of propofol and remifentanil, administered through a target-controlled infusion system, to estimate the optimal concentrations as well as the best way to control the sedative effects induced by the combinations of drugs in patients undergoing ultrasonographic endoscopy. METHODS: One hundred twenty patients undergoing ultrasonographic endoscopy were randomized to receive, by means of a target-controlled infusion system, a fixed effect-site concentration of either propofol or remifentanil of 8 different possible concentrations, allowing adjustment of the concentrations of the other drug. Predicted effect-site propofol (C(e)pro) and remifentanil (C(e)remi) concentrations, parameters derived from auditory evoked potential, autoregressive auditory evoked potential index (AAI/2) and electroencephalogram (bispectral index [BIS] and index of consciousness [IoC]) signals, as well as categorical scores of sedation (Ramsay Sedation Scale [RSS] score) in the presence or absence of nociceptive stimulation, were collected, recorded, and analyzed using an Adaptive Neuro Fuzzy Inference System. The models described for the relationship between C(e)pro and C(e)remi versus AAI/2, BIS, and IoC were diagnosed for inaccuracy using median absolute performance error (MDAPE) and median root mean squared error (MDRMSE), and for bias using median performance error (MDPE). The models were validated in a prospective group of 68 new patients receiving different combinations of propofol and remifentanil. The predictive ability (P(k)) of AAI/2, BIS, and IoC with respect to the sedation level, RSS score, was also explored. RESULTS: Data from 110 patients were analyzed in the training group. The resulting estimated models had an MDAPE of 32.87, 12.89, and 8.77; an MDRMSE of 17.01, 12.81, and 9.40; and an MDPE of -1.86, 3.97, and 2.21 for AAI/2, BIS, and IoC, respectively, in the absence of stimulation and similar values under stimulation. P(k) values were 0.82, 0.81, and 0.85 for AAI/2, BIS, and IoC, respectively. The model predicted the prospective validation data with an MDAPE of 34.81, 14.78, and 10.25; an MDRMSE of 16.81, 15.91, and 11.81; an MDPE of -8.37, 5.65, and -1.43; and P(k) values of 0.81, 0.8, and 0.8 for AAI/2, BIS, and IoC, respectively. CONCLUSION: A model relating C(e)pro and C(e)remi to AAI/2, BIS, and IoC has been developed and prospectively validated. Based on these models, the (C(e)pro, C(e)remi) concentration pairs that provide an RSS score of 4 range from (1.8 µg·mL(-1), 1.5 ng·mL(-1)) to (2.7 µg·mL(-1), 0 ng·mL(-1)). These concentrations are associated with AAI/2 values of 25 to 30, BIS of 71 to 75, and IoC of 72 to 76. The presence of noxious stimulation increases the requirements of C(e)pro and C(e)remi to achieve the same degree of sedative effects.

Prediction of neutropenia-related effects of a new combination therapy with the anticancer drugs BI 2536 (a Plk1 inhibitor) and pemetrexed.

This study investigated the feasibility of predicting the neutropenia-related effects of a therapy that combines the investigational drug BI 2536 (inhibitor of Polo-like kinase 1) and pemetrexed, an approved anticancer drug. Predictions were arrived at using the pharmacokinetic/pharmacodynamic (PK/PD) parameters of each of the drugs obtained from monotherapy studies and assuming that the neutropenic effect is additive when the drugs are administered as a combination therapy. Subsequently, a PK/PD model was developed to determine whether this assumption of additive effect was reasonable in relation to these two drugs. All analyses and simulations were performed using the population approach in NONMEM, version VI.

Effects of fasting and gender on ochratoxin A toxicokinetics in F344 rats.

Ochratoxin A (OTA) is a mycotoxin that causes renal tumors in rats, particularly in males. In previous kinetic studies performed in fed conditions (Vettorazzi et al., 2008), mature F344 male rats presented a significantly lower OTA bioavailability than females and young animals. The objective of the present study was to evaluate two factors which could explain this different kinetic profile: the presence of food and the male-specific protein alpha-2u-globulin. Therefore, a 24h kinetic study has been performed in rats under fasting conditions. Food ingestion has been controlled in both sexes during two months. The presence of alpha-2u-globulin in the urine has been analyzed with SDS-gradient mini-gel electrophoresis. Fasting tends to increase the maximum OTA plasma concentrations and the rate of absorption. The relative bioavailability is significantly increased under fasting conditions only in males. Mature males consumed a higher amount of food but, as the OTA dose administered, it was proportional to body weight. The reason why the OTA bioavailability is more affected in presence of food only in males is unclear. Several possibilities, such as differences in gastric emptying, OTA-food interactions and the involvement of alpha-2u-globulin are discussed.

A different kinetic profile of ochratoxin A in mature male rats.

Ochratoxin A (OTA) is a mycotoxin that causes renal tumors in rodents, particularly in male rats. The present work explored the impact of gender and age on OTA toxicokinetics in F344 rats after a single oral dose (0.5mg/kg b.w.). OTA plasma concentrations were analysed with a validated HPLC-FLD method and a population approach (NONMEM VI) was used to perform the kinetic analysis and the one year exposure simulation (0.21 mg/kg daily). Maximum observed OTA concentration (CMAX(obs)) was at 2h in all groups except in mature females (6h). Mature females reached higher CMAX(obs) than males of the same age. Apparent volume of distribution, but not apparent total plasma clearance, increased significantly with body weight (P<0.01) resulting in the following values for the terminal plasma half life (h) in males: 219 (young), 264 (matures) and females: 191 (young), 205 (matures). In addition mature males showed a significant lower relative bioavailability. The simulation showed similar plasma concentrations in males and females after two-months. Thus, toxicokinetic does not seem to explain sex-differences in toxicity in long-term studies. However, the age and weight should be taken into account in short-term toxicological studies if sex-differences are studied.

Alpha 1-acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome.

OBJECTIVE: To quantify serum protein levels and protein-binding of methadone in vitro in heroin-addicted patients showing objective signs of heroin abstinence. SUBJECTS AND METHODS: Serum samples were obtained from patients (n = 27) hospitalized to participate in a methadone detoxification program and from healthy volunteers (n = 21). The severity of the abstinence syndrome was assessed before blood sampling using a standardized scale. Concentrations of both albumin and alpha1-acid glycoprotein (AAG) were measured in all serum samples. The protein-binding of alpha1-methadone was determined by the ultrafiltration technique and the unbound concentration was measured by liquid scintillation counting. RESULTS: The mean of the AAG concentrations was significantly increased in patients showing signs of withdrawal while the albumin concentrations did not change. Also, the unbound methadone was significantly decreased in this group when compared to the control. A positive correlation (Pearson r = 0.48; p < 0.005) indicates that AAG levels rise during abstinence as the score of withdrawal symptoms increases. Additionally, pooled data from all individuals show the binding of methadone to be related to AAG (r = 0.46; p < 0.05) levels and not to albumin. CONCLUSIONS: The observed changes in protein-binding in abstinence individuals suggest the need for increased dosages of methadone when such patients are treated. Levels of AAG or protein-binding appear to be components of the interindividual variance observed in the response to methadone treatment, hence these variables could be included in future kinetic and dynamic studies.

Serum protein binding of lerisetron, a novel specific 5HT3 antagonist, in patients with cancer.

The aim of this study was, (1) to characterize the serum protein binding of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonist under investigation as an antiemetic agent, and (2) to measure the percentage of unbound lerisetron in cancer patients. The binding parameters were determined in human serum albumin (HSA), alpha1-acid glycoprotein (AAG) and in pooled serum from six healthy volunteers. Concentrations of lerisetron ranging from 50 ng/ml to 2 microg/ml were used. The serum protein binding of 14C-lerisetron (2 microg/ml) was determined by ultrafiltration in three groups of individuals. Group I comprised healthy subjects (n = 11), group II comprised cancer patients undergoing radiotherapy (n = 9), and group III comprised cancer patients receiving chemotherapy (n = 18). The unbound concentration of lerisetron was measured in all samples by liquid scintillation counting. Concentrations of both AAG and HSA were also measured in all serum samples. The drug was extensively bound in pooled serum, involving a nonsaturated process. In HSA, lerisetron was also highly bound (4.04+/-0.8% unbound) and the protein binding was essentially unchanged within the studied concentration range of lerisetron. The extent of binding to AAG was high but significantly lower than in serum and in HSA and was also independent of lerisetron concentration. The unbound lerisetron was significantly decreased in group II cancer patients when compared with group I subjects (2.38+/-0.64% vs 3.70+/-0.70%; P < 0.001). No significant changes in lerisetron binding were observed in group III patients. HSA was diminished in both groups of patients and AAG was only significantly increased in group II. Unbound lerisetron was correlated with AAG in group II and with HSA in group III.

Pharmacokinetics and pharmacodynamics of penbutolol in healthy and cancer subjects: role of altered protein binding.

The pharmacokinetic and pharmacodynamic profiles of penbutolol were examined in healthy volunteers and in cancer patients using a pharmacokinetic/pharmacodynamic (pk/pd) model. After receiving a 40 mg single oral dose of penbutolol, the absorption rate constant, apparent volume of distribution and serum clearance of penbutolol were found to be reduced in the cancer group. Changes in the disposition of the conjugate metabolite were also observed in the cancer patients. Penbutolol unbound fraction in serum was statistically decreased (p < 0.005) in the cancer group, according to the increase in the serum levels of alpha 1-acid glycoprotein seen in that group (p < 0.05). The pharmacodynamic effect of penbutolol was measured as the reduction in heart rate (HR); in healthy volunteers, a linear relationship (p < 0.01) between effect and penbutolol serum concentrations (total or unbound) was found. In contrast, in cancer patients, values of HR did not vary statistically in respect to baseline values. These results show that in cancer patients, a change in the pharmacokinetics of penbutolol occurs (associated with changes in drug protein binding), together with an alteration in the pharmacodynamics.

Semiparametric models for antagonistic drug interactions.

A new class of models to describe antagonistic drug interactions are presented. They are semiparametric in that they use nonparametric functions (splines) but are forced to obey certain constraints corresponding to reasonable assumptions. We propose the models primarily for exploratory data analysis, but they may also be definitive models for such purposes as predicting future responses. Certain problems that arise in semiparametric modeling, such as model selection, are addressed so that we can propose a relatively automatic and objective approach to model determination. We demonstrate the applicability of the class of models we propose to two real data set examples involving pain relief response to opioid agonists/antagonists. The results suggest that the semiparametric approach is particularly useful when unusual shapes link dose to response.

Aging effects on stereoselective pharmacokinetics and pharmacodynamics of verapamil.

Pharmacokinetics and pharmacodynamics were studied after separate single 15-min infusions of each of verapamil's enantiomers (d, 10-11 mg/kg; l, 0.10-0.11 mg/kg) in 16 healthy non-smoking subjects ranging in age from 24 to 40 (young) and from 63 to 83 years (elderly). Verapamil clearance was found to be decreased in an age-related stereoselective manner, with significant reductions in l-verapamil clearance in older subjects (P < .03), but no age-related change in d-verapamil clearance. Greater l- vs. d-verapamil clearance rates were only seen in younger male subjects. Trends for increased elimination half-lives for both enantiomers were seen with increasing age (for d-, P < .09, l- P = .10). Protein binding was stereoselective, with greater binding of d- vs. l-verapamil in both age groups (P < .0001) with no age-related differences in binding detected. Vd beta was greater for d- vs. l-verapamil (P < .05). l-Verapamil was more potent than d-verapamil (P < .001) for all pharmacodynamic variables measured. Both verapamil enantiomers decreased blood pressure (P < .0001), increased P-R intervals during sinus rhythm (P < .0001) and atrioventricular Wenckebach block cycle lengths (P < .0001) and transiently increased heart rate (P < .0001) in both young and elderly subjects. Age-related differences in responses were seen for blood pressure (greater decreases in systolic pressure in the elderly after d-verapamil, P < .002), heart rate (smaller and only transient increases followed by decreases after d-verapamil) and P-R intervals during sinus rhythm (less prolongation in the elderly after both enantiomers, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)