Ivo Caers

EFFECTS OF HIGH DOSE KETOCONAZOLE THERAPY ON THE MAIN PLASMA TESTICULAR AND ADRENAL STEROIDS IN PREVIOUSLY UNTREATED PROSTATIC CANCER PATIENTS

In vitro, ketoconazole has been shown to block testicular and adrenal 17,20‐lyase, which converts progestins to androgens. At higher concentrations, it also inhibits 11β‐hydroxylase, 20,22‐desmolase and 17α‐hydroxylase. To determine the differential hormonal effects of a 2‐week ketoconazole high‐dose therapy, the plasma levels of 10 major androgens, gluco‐ and mineralocorticoids were measured in 14 previously untreated patients with metastatic prostate cancer. Within 24 h, plasma testosterone fell from 14·6 ± 1·4 nmol/l (mean ± SEM) to 3·7 ± 0·7 nmol/l. Thereafter, it decreased to about 2·5 nmol/l and remained at that level. Plasma androstenedione and dehydroepiandrosterone decreased more gradually, respectively from 3·1 ± 0·4 nmol/l to 0·64 ± 0·17 nmol/l and from 6·6 ± 1·0 nmol/l to 2·82 ± 0·55 nmol/l (on day 14). In contrast, 17α‐hydroxyprogesterone and progesterone rose respectively 2‐ and 5‐fold. Plasma cortisol and aldosterone levels remained unchanged whereas 11‐deoxycorticosterone and 11‐deoxycortisol rose by factors of 14 and 6·7 respectively. Plasma corticosterone also increased, but to a much lesser extent (3‐fold). These results demonstrate that ketoconazole high dose therapy blocks mainly the 17,20‐lyase of both adrenal and testis. In addition it inhibits mitochondrial 11β‐hydroxylase to a lesser extent. The inhibition of 20,22‐desmolase also seems to be of little clinical relevance. However, since clinical or laboratory symptoms suggestive of hypo‐adrenalism have been reported in a small minority of patients, replacement therapy should be considered in such cases.

Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17β-oestradiol levels in healthy male volunteers

SummaryThe effect of a single oral dose of 400 mg ketoconazole, given as an 80 mg/ml suspension, on total and physiologically free (i.e. non-sex hormonebound) testosterone and 17β-oestradiol has been investigated in 6 healthy male volunteers. The two steroids fell to nadir levels of 18 and 60% of their respective initial concentrations 6 hours after drug intake, and then completely recovered. Although in vitro slight displacement of testosterone from the sex-hormone binding globulin, by high doses of ketoconazole was found, the physiologically free concentration of testosterone in vivo was closely correlated with that of the total hormone, suggesting that there is no direct interference with sex-hormone binding globulin in vivo. Plasma LH and FSH were not significantly modified by treatment. The effect of ketoconazole on plasma oestradiol levels was less pronounced and was not clearly related to a block of the aromatase system, as reported in vitro.

Determinants of antipsychotic response in schizophrenia: implications for practice and future clinical trials.

BACKGROUND Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials. OBJECTIVE We aimed to understand determinants of response to antipsychotic treatment. METHOD Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580). RESULTS While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented. CONCLUSIONS Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments.

Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia

A number of pharmacological agents for treating negative symptoms in schizophrenia are currently in development. Unresolved questions regarding the design of clinical trials in this area were discussed at an international meeting in Florence, Italy in April 2012. Participants included representatives from academia, the pharmaceutical industry, and the European Medicines Agency (EMA). Prior to the meeting, participants submitted key questions for debate and discussion. Responses to the questions guided the discussion during the meeting. The group reached agreement on a number of issues: (1) study subjects should be under the age of 65; (2) subjects should be excluded for symptoms of depression that do not overlap with negative symptoms; (3) functional measures should not be required as a co-primary in negative symptom trials; (4) information from informants should be included for ratings when available; (5) Phase 2 negative symptom trials should be 12weeks and 26weeks is preferred for Phase 3 trials; (6) prior to entry into a negative symptom study, subjects should demonstrate clinical stability for a period of 4 to 6months by collection of retrospective information; and (7) prior to entry, the stability of negative and positive symptoms should be confirmed prospectively for four weeks or longer. The participants could not reach agreement on whether predominant or prominent negative symptoms should be required for study subjects.

Combining efficacy and completion rates with no data imputation: A composite approach with greater sensitivity for the statistical evaluation of active comparisons in antipsychotic trials

Outcomes in RCTs of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCTs. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p ≤ .05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question.