Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies

Abstract In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials

A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic–pharmacodynamic (PK–PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK–PD models were evaluated. A previously developed PK model was used. An indirect response PK–PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class

A woman with recurrent "infections" since birth--a new mevalonate kinase mutation.

A tired 32-year-old woman complaining of tiredness was referred for work-up of a possible immune deficiency. She had a history of recurrent infections since birth, which usually responded to antibiotics within a few days. Her mother, a nurse, had reported that early charts had disappeared. Munchausen's by proxy was suspected for years. Careful anamnesis indicated possible recurrent fever. Serum IgD levels were high, which led us to suspect Hyper IgD Syndrome. Sequencing of the mevalonate kinase gene revealed 2 mutations, leading to amino acid substitutions: one already described (V3771) and R40W: never reported before. Mevalonate kinase activity was very low in the patient's peripheral blood cells. We used the "Poly Phen" prediction program successfully. Our experiments confirmed the diagnosis of mevalonate kinase deficiency. We used steroids to abort recurrent crises.Case ReportsJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients.

International audienceOBJECTIVE: S-1 is an oral anticancer agent combining tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with potassium oxonate (oteracil) and gimeracil (CDHP) respectively to mitigate gastrointestinal toxicity and increase the half-life of 5-FU. This article presents a population pharmacokinetic analysis of these four compounds in Western cancer patients. The second objective was to compare the pharmacokinetics of S-1 in Western and Japanese patients. METHODS: A single dose (25-45 mg/m2) of S-1 was administered to 60 patients. In each patient, 6 concentrations of FT, 5-FU, oteracil and CDHP were measured over 24 hr. Using NONMEM, oteracil and CDHP were analyzed separately, and the individual estimates of CDHP parameters were included in the joint analysis of FT and 5-FU. We used validation techniques to assess differences between the two populations, and finally we compared the exposures in Western and Japanese patients using simulations. RESULTS: A compartmental model describing the PK of the 4 compounds was developed. The influence of CDHP on the elimination of 5-FU was well described by an enzymatic inhibition model. The model provided a good fit for all compounds. The pharmacokinetics for 5-FU and oteracil were similar between Western and Japanese patients, but apparent differences in exposure to 5-FU resulted from different total doses due to different body sizes

Phase II study of rhizoxin in squamous cell head and neck cancer

To test the anti-tumour activity of rhizoxin in recurrent and/or metastatic squamous cell head and neck cancer, we performed a phase II study. Eligibility required histologically proven squamous cell head and neck cancer. Patients could only have received one prior chemotherapy. Patients were entered if WHO PS was ≤ 2 and organ functions were normal. Treatment consisted of rhizoxin 1.5-2.0 mg m-2 i.v. bolus injection once every 3 weeks. Thirty-two patients entered the study. All were eligible, 31 were evaluable for toxicity and 25 for response. Toxicity mainly consisted of pain at the tumour site and leucocytopenia. Mild asthenia and stomatitis were also observed. Two objective partial responses, lasting 7.5 and 3.5 months, were seen. Rhizoxin at this dose and schedule has minor activity in recurrent and/or metastatic squamous cell head and neck cancer.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer.

BACKGROUND: Because of the relative scarcity of natural paclitaxel (Taxol), which has been recently recognized as a highly cytotoxic agent for use in platinum-refractory ovarian cancer, synthetic and semisynthetic substitutes have been actively pursued. Docetaxel (Taxotere), a new semisynthetic taxoid, has been selected for clinical development because it is twice as potent as paclitaxel in promoting assembly of tubulin and in inhibiting microtubule depolymerization. Docetaxel also shows equal or greater cytotoxicity in relevant preclinical models. PURPOSE: Because docetaxel has produced consistent antitumor responses in ovarian cancer patients in phase I trials, we planned and conducted a phase II clinical trial to evaluate the drug's effectiveness and its toxic effects. METHODS: The present trial, which started in May 1992 and ended in December 1992, involved 97 patients with advanced epithelial ovarian cancer. The target study population had disease relapse or disease progression within 12 months of the last administration of a first-line or second-line platinum-based regimen with at least one bidimensionally measurable target lesion. The patients received docetaxel at a dose of 100 mg/m2 given as a 1-hour infusion every 3 weeks without premedication for minimizing potential hypersensitivity. Docetaxel-induced side effects were graded according to the National Cancer Institute's Common Toxicity Criteria. RESULTS: The overall response rate was 23.6% in 76 assessable patients versus 20% if all 90 eligible patients were included in the comparison (95% confidence interval [CI] = 11%-29%). Among 34 eligible patients whose tumor progressed on the most recent platinum treatment, the response rate was 23.5% (95% CI = 8%-39%). The median progression-free survival for all eligible patients was 3.9 months, and the median overall survival was 8.4 months. Docetaxel-associated toxicity in 90 assessable patients consisted of short-lived neutropenia in 81 (90%) patients, which was complicated by fever and hospitalization in seven (8%); hypersensitivity reactions were seen in 29 (31%) patients, with significant reactions seen in seven (8%); and neurotoxicity in 43 (48%) patients, with grade 3 or above toxicity seen in only three (3%). The treatment also produced skin reactions in 58 (64%) patients, of whom only four (4%) showed the intensity of grade 3. Eleven (12%) patients experienced pleural effusions, which were the effects of the drug considered to be of greatest concern. Peripheral edema and weight gain due to fluid retention were reported in 40 (44%) and 17 (19%) patients, respectively. CONCLUSION: Docetaxel appears to be effective in the treatment of platinum-refractory ovarian cancer patients.Clinical TrialJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe