Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study.

PURPOSE: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. PATIENTS AND METHODS: Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. RESULTS: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). CONCLUSIONS: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).

Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study.

Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Clinical Pharmacokinetics and Pharmacodynamics of the Selective Progesterone Receptor Modulator Vilaprisan: A Comprehensive Overview.

Vilaprisan is a highly potent selective progesterone receptor modulator in development for the treatment of symptomatic uterine fibroids and endometriosis. Its pharmacokinetics are characterized by rapid absorption, almost complete bioavailability, and dose-proportional exposure. The intrinsic factors of age, bodyweight, and race have no clinically relevant effect on the pharmacokinetics and pharmacodynamics of vilaprisan and do not warrant a dose adjustment. Similarly, vilaprisan can be used in patients with mild or moderate renal or hepatic impairment without dose adjustment, but its use is not recommended in patients with severe organ impairment. Vilaprisan has no perpetrator potential on cytochrome P450 (CYP) enzymes or transporters and therefore restrictions in the concomitant use of their substrates are not required. Nonetheless, because it is a sensitive CYP3A4 substrate itself, concomitant use of vilaprisan with strong CYP3A inhibitors or inducers is not recommended. However, there is no risk for QTc prolongation when vilaprisan and a strong CYP3A inhibitor are administered concomitantly, as indicated by a vilaprisan concentration-QTc response analysis across all studies with triplicate electrocardiogram measurements. Furthermore, due to its mode of action, vilaprisan is also not recommended to be used together with progestin-containing oral contraceptives. Vilaprisan shows a steep exposure-response relationship for inducing amenorrhea in patients with uterine fibroids experiencing heavy menstrual bleeding. Based on simulations, a dose of 2 mg/day is expected to induce a maximum bleeding reduction and was thus selected for phase III.

Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure-response modelling and simulation.

AIMS: We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids. METHODS: A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady-state AUC) and IA after oral administration of 0.5, 1, 2 or 4 mg/day over 3 months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2 mg/day. The exposure-E2 relationship was analysed visually. RESULTS: Vilaprisan clearance was 22.7% lower in obese vs non-obese patients. The E-R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (Pmax ) of 59% (95% CI: 49-68%). The exposure at which 50% of Pmax is obtained was 36.9 µg*h/L (95% CI: 27.7-48.7 µg*h/L). Simulations showed that 36% of the patients will be below 90% of Pmax for IA after 1 mg/day compared to 2% after 2 mg/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long-term studies. CONCLUSIONS: A 2 mg/day dose was selected for Phase 3 as E-R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.

Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies.

BACKGROUND: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. PATIENTS AND METHODS: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m2) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model. RESULTS: Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60-93 mg/m2). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m2. The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand-foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. CONCLUSIONS: The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m2. Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. CLINICAL TRIAL NUMBER: NCT02085148.

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake.

AIM: Regorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M-2 and M-5 in solid tumours. METHODS: The model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib. This was then applied to sparsely sampled data from four phase 3 studies in patients with advanced solid tumours. The need for exact food intake data to estimate individual drug exposure was evaluated. RESULTS: By incorporating EHC, the model adequately described the PK profiles of regorafenib, M-2 and M-5 after single and multiple doses in patients from phase 1 studies. Individual exposure in phase 3 studies was adequately described based on assumptions on the time and frequency of food intake, although exact food intake data are recommended to improve the estimation. Covariate analysis identified sex and body mass index (BMI) as impacting exposure to regorafenib, and sex as strongly impacting exposure to M-2 and M-5 (also influenced by the BMI effect on parent regorafenib in the joint model developed); however, these factors accounted for a small portion of the overall variability in exposure. CONCLUSIONS: The adequate description of regorafenib PK after multiple dosing requires the incorporation of EHC. Neither single nor combined covariates predicted exposures that would warrant a priori regorafenib dose adjustment.

Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer.

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships. Time-to-event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose-reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand-foot skin reactions).

Characterization and Prediction of Cardiovascular Effects of Fingolimod and Siponimod Using a Systems Pharmacology Modeling Approach.

Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model to identify the site of action (i.e., primary hemodynamic response variable) of S1P receptor agonists, and to predict, in a quantitative manner, the cardiovascular effects of novel S1P receptor agonists in vivo. The cardiovascular effects of once-daily fingolimod (0, 0.1, 0.3, 1, 3, and 10 mg/kg) and siponimod (3 and 15 mg/kg) were continuously recorded in spontaneously hypertensive rats and Wistar-Kyoto rats. The results were analyzed using a recently developed systems cardiovascular pharmacology model, i.e. the CVS model; total peripheral resistance and heart rate were identified as the site of action for fingolimod. Next, the CVS model was interfaced with an S1P agonist pharmacokinetic-pharmacodynamic (PKPD) model. This combined model adequately predicted, in a quantitative manner, the cardiovascular effects of siponimod using in vitro binding assays. In conclusion, the combined CVS and S1P agonist PKPD model adequately describes the hemodynamic effects of S1P receptor agonists in rats and constitutes a basis for the prediction, in a strictly quantitative manner, of the cardiovascular effects of novel S1P receptor agonists.

Model-Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms.

Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects. Population PK models for ATZ and LNG were established where the interaction of LNG with sex hormone-binding globulin (SHBG) as well as a stimulating effect of estradiol on SHBG were considered. Furthermore, simulations showed that doses of 40 µg/d LNG combined with 300, 600, or 1050 µg/d ATZ reached anticipated exposure levels for both drugs, facilitating selection of ATZ and LNG doses in the phase 2 dose-finding study. The main driver for the effect on maximum follicle size appears to be unbound LNG exposure. A 50% probability of maximum follicle size ≥30 mm was estimated for 40 µg/d LNG based on the exposure-response analysis. ATZ in the dose range investigated does not increase the risk for ovarian cysts as occurs with LNG at a dose that does not inhibit ovulation.

Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients.

AIMS: This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODS: Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. RESULTS: Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%). CONCLUSIONS: Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.

Translational pharmacokinetic modeling of fingolimod (FTY720) as a paradigm compound subject to sphingosine kinase-mediated phosphorylation.

A complicating factor in the translational pharmacology of sphingosine 1-phosphate agonists is that they exert their pharmacological effect through their respective phosphate metabolites, which are formed by the enzyme sphingosine kinase (S1PHK). In this investigation, we present a semimechanistic pharmacokinetic model for the interconversion of S1PHK substrates and their respective phosphates in rats and humans with the aim of investigating whether characterization of the rate of phosphorylation in blood platelets constitutes a basis for interspecies scaling using fingolimod as a model compound. Data on the time course of fingolimod and fingolimod-phosphate (fingolimod-P) blood concentrations after intravenous and oral administration of fingolimod and/or fingolimod-P in rats and after oral administration of fingolimod in doses of 0.5, 1.25, and 5 mg once daily in healthy volunteers were analyzed in conjunction with data on the ex vivo interconversion and blood-plasma distribution in rat and human blood, respectively. Integrating the data from the ex vivo and in vivo studies enabled simulation of fingolimod and fingolimod-P concentrations in plasma rather than blood, which are more relevant for characterizing drug effects. Large interspecies differences in the rate of phosphorylation between rats and humans were quantified. In human, phosphorylation of fingolimod in the platelets was four times slower compared with rat, whereas the dephosphorylation rates were comparable in both species. This partly explained the 10-12-fold overprediction of fingolimod-P exposure in human when applying a dose-by-factor approach on the developed rat model. Additionally, differences in presystemic phosphorylation should also be taken into account.

Nonlinear mixed effects modeling of the diurnal blood pressure profile in a multiracial population.

BACKGROUND: Cardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling. METHODS: Ambulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability. RESULTS: The diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R (2) = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks. CONCLUSIONS: The developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABPM.

The virtue of translational PKPD modeling in drug discovery: selecting the right clinical candidate while sparing animal lives.

Translational pharmacokinetic-pharmacodynamic (PKPD) modeling has been fully implemented at AstraZeneca's drug discovery unit for central nervous system and pain indications to facilitate timely progression of the right compound to clinical studies, simultaneously assuring essential preclinical efficacy and safety knowledge. This review illustrates the impact of a translational PKPD paradigm with examples from drug discovery programs. Paradoxically, laboratory animal use decreased owing to better understanding of in vitro-in vivo relationships, optimized in vivo study designs, meta-analyses and hypothesis testing using simulations. From an ethical and effectivity perspective, we advocate that translational PKPD approaches should be implemented more broadly in drug discovery.

Pharmacokinetic-pharmacodynamic modeling of the antihypertensive effect of eprosartan in Black and White hypertensive patients.

BACKGROUND AND OBJECTIVE: It is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic-pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated. PATIENTS AND METHODS: Eprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1 ± 7.6 years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling. RESULTS: Eprosartan concentration-time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80 % of the maximum decrease in SBP was observed after 24 days. Interindividual variability in drug response was 65 % and decreased to 14 % when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [-2.6 mm Hg per (ng/ml)]. CONCLUSIONS: The developed pharmacokinetic-pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.

Evaluation of the impact of UGT polymorphism on the pharmacokinetics and pharmacodynamics of the novel PPAR agonist sipoglitazar.

Sipoglitazar is a peroxisome proliferator-activated receptor α, δ, and γ agonist. During phase I, a wide distribution of clearance between individuals was observed. Hypothesized to result from a polymorphism in the uridine 5'-diphospate-glucuronosyltransferase (UGT)2B15 enzyme, pharmacogenetic samples were collected from each individual for genotyping UGT2B15 in a subsequent phase I trial in healthy subjects (n = 524) and in 2 phase II trials in type 2 diabetes subjects (n = 627), total genotype frequency was as follows: *1/*1 (22%), *1/*2 (51%), and *2/*2 (27%). The impact of genotype on exposure was assessed using a pharmacokinetic modeling approach; the influence of genotype on efficacy was evaluated using 12-week HbA1c change from baseline. Model analysis demonstrated UGT2B15 genotype accounted significantly for the variability in sipoglitazar clearance; however, a small fraction of subjects had a clearance that could not be explained entirely by genotype. HbA1c drop increased with daily drug dose. When stratified by both dose and genotype, HbA1c drop was larger in the UGT2B15*2/*2 compared with UGT2B15*1/*1 and UGT2B15*1/*2 genotypes (P < .05). In summary, UGT2B15 genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the UGT2B15*2/*2 genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype.

Predicting human exposure of active drug after oral prodrug administration, using a joined in vitro/in silico-in vivo extrapolation and physiologically-based pharmacokinetic modeling approach.

INTRODUCTION: Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice. In this paper, a joined in vitro/in silico-in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modeling approach is presented to predict active drug exposure in human after oral prodrug administration. METHODS: Physico-chemical and in vitro assays as well as in silico predictions were proposed to characterize key pharmacokinetic properties (e.g. clearance, volume of distribution, conversion rates) of three marketed prodrugs. These data were used to parameterize a PBPK model for simulating human PK profiles of the active drugs after prodrug administration, which were compared to literature data by evaluating the accuracy and uncertainty of the predictions. RESULTS: For mycophenate mofetil and midodrine the PK of their active moieties could be adequately predicted. The assumptions of the PBPK-IVIVE approach were valid, i.e. being hepatically cleared, converted in the gut lumen, blood and liver and not metabolized in the gut wall. However, the observed profiles after oral bambuterol administration clearly fell outside the prediction interval as the PBPK model failed to predict the observed bioavailability. DISCUSSION: Adding quantitative information about prodrug conversion in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion (ADME) properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood. Also in a prospective compound selection process, this integrative approach can improve decision making on prodrug candidates by putting relative differences in prodrug conversion of a large number of candidates into the perspective of their human PK profile, before conducting any in vivo experiments.

Mechanism-based PK-PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans.

The aim of this investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound. After assessment of baseline variation in prolactin concentrations, the prolactin response of remoxipride was measured following (1) single intravenous doses of 4, 8 and 16 mg/kg and (2) following double dosing of 3.8 mg/kg with different time intervals. The mechanistic PK-PD model consisted of: (i) a PK model for remoxipride concentrations in brain extracellular fluid; (ii) a pool model incorporating prolactin synthesis, storage in lactotrophs, release into- and elimination from plasma; (iii) a positive feedback component interconnecting prolactin plasma concentrations and prolactin synthesis; and (iv) a dopamine antagonism component interconnecting remoxipride brain extracellular fluid concentrations and stimulation of prolactin release. The most important findings were that the free brain concentration drives the prolactin release into plasma and that the positive feedback on prolactin synthesis in the lactotrophs, in contrast to the negative feedback in the previous models on the PK-PD correlation of remoxipride. An external validation was performed using a dataset obtained in rats following intranasal administration of 4, 8, or 16 mg/kg remoxipride. Following simulation of human remoxipride brain extracellular fluid concentrations, pharmacodynamic extrapolation from rat to humans was performed, using allometric scaling in combination with independent information on the values of biological system specific parameters as prior knowledge. The PK-PD model successfully predicted the system prolactin response in humans, indicating that positive feedback on prolactin synthesis and allometric scaling thereof could be a new feature in describing complex homeostatic mechanisms.

Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration.

Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport route from the nasal cavity into the brain exists. Pharmacokinetic modeling is proposed to identify the existence of direct nose-to-brain transport in a quantitative manner. The selective dopamine-D2 receptor antagonist remoxipride was administered at different dosages, in freely moving rats, by the IN and intravenous (IV) route. Plasma and brain extracellular fluid (ECF) concentration-time profiles were obtained and simultaneously analyzed using nonlinear mixed-effects modeling. Brain ECF/plasma area under the curve ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multicompartment pharmacokinetic model with two absorption compartments (nose-to-systemic and nose-to-brain) was found to best describe the observed pharmacokinetic data. Absorption was described in terms of bioavailability and rate. Total bioavailability after IN administration was 89%, of which 75% was attributed to direct nose-to brain transport. Direct nose-to-brain absorption rate was slow, explaining prolonged brain ECF exposure after IN compared with IV administration. These studies explicitly provide separation and quantitation of systemic and direct nose-to-brain transport after IN administration of remoxipride in the rat. Describing remoxipride pharmacokinetics at the target site (brain ECF) in a semiphysiology-based manner would allow for better prediction of pharmacodynamic effects.

Mitotane has a strong and a durable inducing effect on CYP3A4 activity.

OBJECTIVE: The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib. DESIGN: A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment. RESULTS: The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC(0)(-)(12 h) (95% CI): 7.6 (5.5-9.7) vs 139.0 (95.1-182.9) µg×h/l respectively P=0.001) and increased 1-hydroxy-midazolam exposure (mean AUC(0)(-)(12 h) (95% CI): 409.6 (290.5-528.7) vs 35.0 (26.4-43.6) µg×h/l, P=0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 µg×h/l versus 1344 (1079-1609) (mean (95% CI)) µg×h/l). CONCLUSION: Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzyme.

Marginal increase of sunitinib exposure by grapefruit juice.

PURPOSE: The drug label of sunitinib includes a warning for concomitant use of grapefruit juice (GJ) but clinical evidence for this drug interaction is lacking. The aim of this study is to determine the effect of GJ, a potent intestinal cytochrome P450 (CYP) 3A4 inhibitor, on steady-state sunitinib pharmacokinetics (PK). METHODS: Sunitinib PK was evaluated in eight cancer patients receiving sunitinib monotherapy in a "4 weeks on-2 weeks off" dose regimen. Serial blood samples for PK analysis of sunitinib were collected on two separate days. On both PK days, patients received a single oral dose of 7.5-mg midazolam as a phenotypic probe for assessment of intestinal CYP3A4 activity. The first PK day was at steady-state sunitinib PK (between days 14-20), the second PK day was on day 28. On days 25, 26 and 27, 200-mL GJ was consumed 3 times a day. The effect of GJ on sunitinib exposure was assessed by comparing sunitinib PK with and without GJ. RESULTS: Concomitant use of GJ and sunitinib resulted in an 11% increase of the relative bioavailability of sunitinib (P < 0.05). The effect of GJ on CYP3A4 activity was confirmed by an increase of ~50% of mean midazolam exposure (AUC(0-24 h)) from 122.1 to 182.0 ng h/mL (P = 0.034). CONCLUSION: GJ consumption results in a marginal increase in sunitinib exposure which is not considered clinically relevant. There is no clinical evidence underscoring the warning in the sunitinib drug label regarding concomitant use of GJ.