Exploratory IND: a new regulatory strategy for early clinical drug development in the United States.

Optimizing exploratory drug development by means of doing first-in-human studies earlier is an attractive option for pharmaceutical sponsors to select more successful drug candidates. Traditional registration-driven clinical phase 1 programs could be preceded by early human screening studies with subpharmacological single doses (microdoses) or with low pharmacologically active doses of one or several lead candidates, whereby human pharmacokinetic and pharmacodynamic data are generated very early. Such low doses are not expected to have clinically significant toxic potential, so early human screening studies may be supported by abbreviated nonclinical safety packages. Recent U.S. FDA draft guidance (April 2005) regulated early human screening studies conducted under the exploratory IND. The author outlines the features of the study design, dose selection, and nonclinical safety packages required in support of exploratory IND studies in humans. In appropriately chosen cases, exploratory IND could allow for patients' quicker access to safer and more efficacious doses of novel drugs, reduce attrition in clinical trials, and facilitate more economical drug development.

Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

Pharmacokinetic changes in patients with oedema.

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma.

PURPOSE: This study characterized the multiple-dose pharmacokinetics of vemurafenib 240-960 mg twice daily (bid) in BRAF(V600E) mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets). METHODS: Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2. RESULTS: Vemurafenib concentration increased with multiple doses to steady state at day 15; C(max), AUC(0-8h), and AUC(0-168h) increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240-960 mg bid. Day 15 mean accumulation ratios (ratio of AUC(0-8h) on day 15/AUC(0-8h) on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration-time profile throughout the bid dosing interval. During dose interruption (days 15-22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5-38.4 h. CONCLUSIONS: Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C(max)) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

Ritonavir 100 mg does not cause QTc prolongation in healthy subjects: a possible role as CYP3A inhibitor in thorough QTc studies.

To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.