Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014).

Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.

Estimating the contribution of everolimus to immunosuppressive efficacy when combined with tacrolimus in liver transplantation: a model-based approach.

Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when "placebo control" data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric-based exposure-response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling. The efficacy contribution of everolimus was then demonstrated by comparing this prediction to the efficacy of the combination regimen. This pharmacometrics-based approach may contribute to characterization of therapeutic agents in real-world settings.

mTOR inhibition in liver transplantation: how to dose for effective/safe CNI reduction?

Everolimus (EVR) is a semi-synthetic mammalian target of rapamycin inhibitor currently under development for liver transplantation (LTx) in combination with reduced exposure tacrolimus (rTAC). The relative potency of EVR was assessed in order to generate evidence for concomitant EVR+rTAC exposure in LTx recipients (LTxR). Twelve month data from study H2304 (NCT00622869), a 24-month, randomized, multicenter study in 719 de novo LTxR comparing EVR+rTAC to standard TAC demonstrated superior renal function and comparable efficacy, including fewer and less severe biopsy proven acute rejections with EVR+rTAC. Relative potency (p) of EVR was defined as factor by which the effect of 1 ng/mL of EVR must be multiplied to get comparable immunosuppression as with TAC: p = (TACcon - TACred)/EVRred. Relative efficacy of EVR in 4 different subpopulatlons was consistently 0.64, 0.60, 0.69, and 0.62, respectively. This assessment determined the relative potency of EVR as 0.64 compared to TAC in LTx indicating that EVR and TAC are not equipotent per ng/mL exposure. Knowledge about relative potency will help to rationalize co-exposure of EVR and TAC.

Deferasirox does not induce QT/QTc-prolongation in healthy subjects.

UNLABELLED: The International Conference on Harmonization (ICH) E14 guidance recommends that almost all drugs should undergo careful clinical testing in a thorough QT/QTc study. Deferasirox (Exjade, ICL670) is a once-daily oral iron chelator, developed for the treatment of blood transfusion-related iron overload. OBJECTIVE: This study was designed to investigate the effect of deferasirox on the QT/QTc interval. METHODS: A randomized, single-dose, placebo- and positive-controlled, parallel-group study was conducted in a total of 182 healthy subjects. Study participants were randomized to four treatments arms: deferasirox 20 mg/kg (n = 46), deferasirox 40 mg/kg (n = 46), placebo (n = 46) or moxifloxacin 400 mg (n = 44). Moxifloxacin tablets were taken in an open-label fashion, while the subjects and investigator staff remained blinded for the other treatments. Electrocardiograms, obtained at various time points during a 24-h period, were evaluated centrally in a blinded fashion. The primary endpoint was the average change from baseline in QT/QTc over the 24-h period following intake of study medication. It was prospectively defined that deferasirox will be considered devoid of inducing QT/QTc-prolongation if the upper bound of the 95% 2-sided confidence interval (CI) for the difference to placebo is below 8 milliseconds (i.e., being noninferior to placebo). RESULTS: Deferasirox 20 and 40 mg/kg were noninferior to placebo with respect to the average change from baseline in QT/QTc, as indicated by 95% CIs for the mean treatment difference (deferasirox 20 or 40 mg/kg minus placebo), which were entirely below 8 milliseconds. The lower limit of the 95% 2-sided CI for the difference between moxifloxacin and placebo was greater than 0 milliseconds, demonstrating the sensitivity of the study. Deferasirox C(max) and AUC following intake of deferasirox 40 mg/kg was higher by factor 1.6 and 2.3, respectively, than observed at a steady state in beta-thalassemia patients treated for 6 months with deferasirox 30 mg/kg, the recommended maximum dose. CONCLUSIONS: This study demonstrates that deferasirox does not prolong the QT/QTc interval at both therapeutic and supratherapeutic plasma concentrations. It is, therefore, not expected that deferasirox has a negative effect on cardiac repolarization in patients under treatment with this medication.

Relative bioavailability of deferasirox tablets administered without dispersion and dispersed in various drinks.

UNLABELLED: Deferasirox (ExjadeA, ICL670) is a new, once-daily oral iron chelator, recently approved as first-line therapy in the treatment of iron overload resulting from blood transfusions. In registration studies, deferasirox tablets were dispersed in non-carbonated water prior to administration. In routine clinical practice, however, patients may prefer to take the tablet dispersed in a flavored drink rather than with water. OBJECTIVE: Stability and compatibility tests were performed to identify beverages suitable for the dispersion of tablets for further testing in man. This was followed by a pharmacokinetic study to assess the relative bioavailability of deferasirox tablets dispersed in two types of soft drinks, dispersed in water, and without dispersion. METHODS: An open-label, randomized, 4-period, crossover study was carried out with 28 healthy volunteers who received single 20 mg/kg oral doses of deferasirox without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in non-carbonated water (reference). Deferasirox and Fe-[deferasirox]2 were measured in plasma using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were compared using standard bioequivalence tests. RESULTS: Mean deferasirox AUC0-t were 1,040 A+/- 530, 1,010 A+/- 278, 882 A+/- 252 and 996 A+/- 352 h x micromol/l when deferasirox tablets were administered without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in water, respectively, indicating that these forms of deferasirox administrations met bioequivalence criteria. Therefore, the oral bioavailability of deferasirox tablets was not affected neither by the degree of dispersion nor by the type of drink (orange or apple juice versus water) used for dispersion. CONCLUSIONS: This study shows that deferasirox bioavailability is unaltered when dispersed with orange or apple juice compared with dispersion in water. Thus, in addition to water, patients have the option of taking deferasirox tablets in orange or apple juice. The degree of dispersion did not affect deferasirox bioavailability. Therefore, deferasirox therapy will not be compromised if dispersion of the tablet is not fully complete; although the latter should be avoided.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators.

OBJECTIVE: The goal of this multicenter, double-blind, randomized, parallel-group study was to compare the effects of losartan potassium (hereafter referred to as losartan), candesartan cilexitil (hereafter referred to as candesartan), and losartan/hydrochlorothiazide (HCTZ) in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] 95-115 mm Hg). METHODS: A total of 1161 patients were randomized in a 2:2:1 ratio to 12 weeks of treatment with losartan 50 mg QD, possibly titrated to 100 mg QD (n = 461); candesartan 8 mg QD, possibly titrated to 16 mg QD (n = 468); or losartan 50 mg QD, possibly titrated to losartan 50 mg plus HCTZ 12.5 mg QD (n = 232). At 6 weeks, the regimens of patients not reaching a goal SiDBP <90 mm Hg were titrated as described, whereas patients achieving this goal continued with low-dose monotherapy. The single primary end point at 12 weeks tested the equivalence of the 2 monotherapy regimens, predefined as a maximum between-treatment difference in the mean change from baseline trough SiDBP of 2.5 mm Hg. RESULTS: At 12 weeks, changes in SiDBP/sitting systolic blood pressure (SiSBP) of -12.4/-14.4 mm Hg with losartan 50 mg/100 mg and -13.1/-15.8 mm Hg with candesartan 8 mg/16 mg demonstrated equivalence between the 2 monotherapy regimens (95% CI for difference in SiDBP, -1.6 to 0.2). At 12 weeks, the losartan 50 mg/50 mg plus HCTZ 12.5 mg regimen had reduced SiDBP/SiSBP significantly more (-14.3/-18.0 mm Hg) than either the candesartan 8 mg/16 mg (SiDBP, P = 0.045; SiSBP, P = 0.017) or losartan 50 mg/100 mg regimen (SiDBP and SiSBP, P = 0.001). During the last 6 weeks, patients whose regimen had been titrated to losartan 50 mg plus HCTZ 12.5 mg (n = 114) showed a greater reduction in SiDBP/SiSBP (-14.5/ -18.7 mm Hg) than did those whose regimen had been titrated to either losartan 100 mg (-10.5/-12.3 mm Hg; n = 211) or candesartan 16 mg (-11.5/-13.2 mm Hg; n = 206), representing a clinically meaningful > or = 2.5-mm Hg) difference. All 3 treatments were well tolerated, with few patients experiencing drug-related adverse events (6.9% losartan 50 mg/100 mg, 7.5% candesartan 8 mg/16 mg, 3.0% losartan 50 mg/ 50 mg plus HCTZ 12.5 mg). Candesartan 8 mg/16 mg increased serum uric acid levels (0.13 mg/dL; 95% CI, 0.04 to 0.23), whereas losartan 50 mg/100 mg decreased them (-0.14 mg/dL; 95% CI, -0.24 to -0.04), and losartan 50 mg/50 mg plus HCTZ 12.5 mg left them unchanged (0.06 mg/dL; 95% CI, -0.07 to 0.20). CONCLUSIONS: Losartan 50 mg/100 mg and candesartan 8 mg/16 mg were comparable treatments in terms of blood pressure reduction. After titration, losartan 50 mg plus HCTZ 12.5 mg was superior to either candesartan 16 mg or losartan 100 mg in reducing hypertension. Losartan, but not candesartan, lowered serum uric acid levels and attenuated the expected increase in uric acid levels with HCTZ 12.5 mg.

Use of ambulatory blood pressure monitoring to compare antihypertensive efficacy and safety of two angiotensin II receptor antagonists, losartan and valsartan. Losartan Trial Investigators.

The efficacy and safety of losartan and valsartan were evaluated in a multicenter, double-blind, randomized trial in patients with mild to moderate essential hypertension. Blood pressure responses to once-daily treatment with either losartan 50 mg (n = 93) or valsartan 80 mg (n = 94) for 6 weeks were assessed through measurements taken in the clinic and by 24-hour ambulatory blood pressure monitoring (ABPM). Both drugs significantly reduced clinic sitting systolic (SiSBP) and diastolic blood pressure (SiDBP) at 2, 4, and 6 weeks. Maximum reductions from baseline in SiSBP and SiDBP on 24-hour ABPM were also significant with the two treatments. The reduction in blood pressure was more consistent across patients in the losartan group, as indicated by a numerically smaller variability in change from baseline on all ABPM measures, which achieved significance at peak (P = .017) and during the day (P = .002). In addition, the numerically larger smoothness index with losartan suggested a more homogeneous antihypertensive effect throughout the 24-hour dosing interval. The antihypertensive response rate was 54% with losartan and 46% with valsartan. Three days after discontinuation of therapy, SiDBP remained below baseline in 73% of losartan and 63% of valsartan patients. Both agents were generally well tolerated. Losartan, but not valsartan, significantly decreased serum uric acid an average 0.4 mg/dL at week 6. In conclusion, once-daily losartan 50 mg and valsartan 80 mg had similar antihypertensive effects in patients with mild to moderate essential hypertension. Losartan produced a more consistent blood pressure-lowering response and significantly lowered uric acid, suggesting potentially meaningful differences between these two A II receptor antagonists.

Increased efficacy and tolerability with losartan plus hydrochlorothiazide in patients with uncontrolled hypertension and therapy-related symptoms receiving two monotherapies.

The efficacy and tolerability of losartan 100 mg/hydrochlorothiazide (HCTZ) 25 mg and enalapril 10 mg/HCTZ 25 mg were compared in a double-blind, randomized trial in hypertensive patients inadequately controlled and experiencing side effects on prior therapy. Patients with moderate or severe hypertension, currently treated with at least two single-agent drugs (excluding angiotensin-converting enzyme inhibitors), with a sitting diastolic blood pressure (DBP) above 90 mm Hg, and at least one undesirable drug-related symptom were randomized to once-daily treatment with one of the combinations for 12 weeks. Losartan/HCTZ lowered sitting DBP from the prior therapy baseline by 13.7 mm Hg and sitting systolic blood pressure 19.3 mm Hg; similar reductions occurred with enalapril/HCTZ. Trough sitting DBP was reduced to normal levels (< 90 mm Hg) in 63% of patients switched to the losartan combination and in 58% of those treated with the enalapril combination. Each combination was associated with improved tolerability compared with prior therapy, although fewer patients reported each of 24 undesirable symptoms after 12 weeks of losartan/HCTZ. The improvement from prior therapy in the occurrence of cough was significantly greater with losartan/HCTZ (P = .005). Enalapril/HCTZ, but not losartan/HCTZ, increased serum uric acid levels at week 12. In conclusion, the combination of losartan 100 mg/HCTZ 25 mg offers a beneficial therapeutic option for patients with a history of moderate to severe hypertension whose blood pressure is not adequately controlled or who exhibit side effects while on two or more single-agent antihypertensive drugs. In this population, the switch from prior antihypertensive therapies to once daily losartan 100 mg/HCTZ 25 mg improves blood pressure control and reduces side effects.