Ramucirumab (RAM) for sorafenib intolerant patients with hepatocellular carcinoma (HCC) and elevated baseline alpha fetoprotein (AFP): Outcomes from two randomized phase 3 studies (REACH, REACH2).

4073 Background: Oral multikinase inhibitors that have shown improvements in overall survival (OS) in HCC are associated with clinically important toxicities that commonly require dose adjustment or discontinuation (D/C) due to intolerance. REACH and REACH-2 studied RAM in patients (pts) with HCC who progressed on or were intolerant to sorafenib (SOR), and REACH-2 only enrolled pts with baseline AFP ≥400 ng/mL. In REACH-2 RAM treatment (trt) improved OS compared to placebo (P), supporting findings in REACH pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by reason for D/C of SOR was performed. Methods: Pts had advanced HCC, Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or P Q2W. A pooled independent pt data analysis (stratified by study) of REACH-2 and REACH pts (AFP ≥400 mg/mL) was performed. Results are reported by reason for SOR D/C (intolerance or disease progression). OS and PFS were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR) and safety are reported. Results: Baseline characteristics in the pooled population were generally balanced between trt arms in each subgroup. Median durations of prior SOR were 2.5 mo for SOR intolerant (n = 70) and 4.0 mo for SOR progressors (n = 472). Median OS (RAM v P) was 10.2 v 6.7 mo for SOR intolerant and 8.0 v 4.7 mo for SOR progressors (Table). Rates of D/C due to trt-related adverse events (AEs) (Table) (7% in each subgroup), and Grade ≥3 AEs (most frequently hypertension) were consistent with those observed in each study. Conclusions: Acknowledging limitations of sample size, the RAM trt benefit in SOR intolerant pts was consistent with that in the ITT population. RAM was well tolerated in SOR intolerant pts with low rates of D/C due to related-AEs. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]

Drug prescribing

Great care should be exercised when prescribing for children with kidney disease. Many drugs are renally excreted and require dose adjustment in the presence of chronic kidney disease. Children with kidney disease, particularly those who have undergone kidney transplantation, frequently receive a large number of drugs and there is significant potential for drug–drug interaction. Information is available in the British National Formulary for Children and other texts; however, advice from an experienced paediatric nephrologist or specialist renal pharmacist should be sought where there is uncertainty.

The current treatment strategy for gouty arthritis

Febuxostat is a non-purine selective inhibitor of isoforms of xanthine oxidoreductase (XOR), the effect of which is aimed at lowering the level of serum uric acid (UA). Febuxostat is a more potent inhibitor of XOR than allopurinol, as confirmed by that target UA levels have been achieved more frequently with febuxostat than with allopurinol, particularly in patients with high serum urate concentrations. The pharmacokinetic properties of febuxostat are not dependent on renal clearance, which distinguishes it from allopurinol and may benefit patients with chronic kidney disease. A number of studies are being conducted to further evaluate the cardiovascular safety of febuxostat and its possible positive effects in preserving renal function. Of importance is the fact that febuxostat does not require dose adjustment in elderly patients.

Management of Common Side Effects of Apremilast

Apremilast is a relatively new therapy for the treatment of moderate to severe plaque psoriasis in adults. While this medication is considered safe with a very low risk of serious side effects, a few common (≥5% of patients) mild to moderate side effects have been reported, including diarrhea, nausea, headache, and nasopharyngitis. Not addressing these symptoms may lead to medication nonadherence and unnecessary discontinuation of therapy. These side effects are often easily managed with interventions available to the practicing dermatologist, and in only rare instances will these side effects require dose adjustment or discontinuation of therapy. The purpose of this article is to review common side effects of apremilast at its approved dose of 30 mg orally twice daily (BID) and to provide clear, simple recommendations for their management in dermatological practice.

Interaction of antihypertensive drugs and rosuvastatin: focus on safety, efficiency and prospects

Arterial hypertension and dyslipidemia is a very frequent comorbid condition. Arterial hypertension and dyslipidemia are combined in 40-70% of patients. The statins is the basic drug in primary and secondary prevention of cardiovascular disease and in the reduction of cardiovascular complications. We`ve attempted to summarize some data about the statins and interaction of antihypertensive drugs. Rosuvastatin is a medicine that provides an intensive reduction of low-density lipoproteins, does not require dose adjustment when applied in conjunction with antihypertensive drugs. The absence of inhibition and activation of rosuvastatin cytochrome P450 provides a low risk of negative interactions in the clinical situations of induced polypharmacy. Every clinician is to remember that it`s crucial to take into account some adverse reactions combining the statins with drugs of other pharmacological groups.

The study of clinical bioequivalence drug Nativa (generic desmopressin acetate tablets) in patients with central diabetes insipidus

Materials and methods. The study included 15 patients (9 women and 6 men) with central diabetes insipidus (CDI), compensated by therapy with a tablet formulation Minirin (diuresis up to 3000 ml). The average age of the patients was 44 ± 8 years. For 3 days during treatment Minirin we evaluated the clinical manifestations of the CDI. On the fourth day, Minirin was replaced by Nativa in the equivalent dose, with further correction whennecessary. From the 4th to the 6th day of treatment with Nativawe assessed the same parameters as on the initial therapy.Results. The vast majority of patients did not require dose adjustment and, if necessary, dose adjustment was small and accounted for about 20% of the original dose. Average dose did not differ in patients receiving Minirin or Nativa, 0.43 ± 0.26 vs. 0.45 ± 0.32 (p 0.05).Conclusions. Nativa is characterized by therapeutic equivalence to Minirin in patients with a central form of diabetes insipidus.

Association of clofarabine (Clo)-associated GFR decline (GFRd) with dose and AUC.

e13120^ Background: Clo, a nucleoside analog, is approved for pediatric ALL, but also has activity in AML. We conducted a ph I-II trial of clo-melphalan-alemtuzumab for allo transplant and found grade 3-5 renal toxicity in 16 of 74 patients, despite prolonging infusion time to reduce Cmax (BBMT 2011, Epub). Methods: Clo pharmacokinetics were analyzed in 65 pts (Clo doses 10-40 mg/m2, infusion time 1 or 3 hrs) of 74 pts; baseline GFR estimated by modified MDRD equation. Clo levels were drawn at 1, 1.5, 2, 3, 5, 7, 9 and 24 hrs following the 1st and 3rd (or 4th) dose. GFRd (in ml/min/m2) between start of Clo (d-7) and day of transplant constituted the outcome of interest. Results: Median age 53 (21-73), median baseline GFR 94 ml/min/m2 (46-120). Mean (range) Cmax, clearance (CL) and AUC were 531 ng/ml (119-1010), 42002 ml/min (13979-88020) and 2052 ng*hr/ml (471-5835), respectively. Mean AUC per dose was 32.0 ng*hr/ml/mg (14-32). Systemic exposure was similar between d1 and d3. Further analyses used the highest AUC and Cmax. Decreases in GFR ranging from 10-100 ml/min/m2 (average 44 ml/min/m2) occurred in 30 of 65 patients. There was no correlation between Clo dose and GFRd (r=-0.02,p=0.87). There was a significant correlation between Clo AUC and GFRd (r=0.53, p <0.0001), Clo AUC per dose and GFRd (r=0.62, p<0.001) and between Clo CL and GRFd (r=-0.38, p=0.0001). There was a weaker correlation between Clo Cmax and GFRd (r=0.22, p=0.07). Clo CL was highly correlated with baseline GFR (r=0.4, p=0.0009). Of interest baseline GFR was inversely correlated with pt age (r=-0.46, p=0.0001) and age was significantly correlated with AUC (r=0.4, p=0.001), AUC per dose (r=0.36, p=0.003) and with GFRd (r=0.34, p=0.005). Conclusions: Decline in GFR is associated with inter-patient variability in exposure to Clo. Baseline GFR affects Clo CL and thus AUC, and potentially increases risk for renal toxicity. Older age is associated with decreased baseline GFR and risk for toxicity. Clo may require dose adjustment based upon renal function and/or age. These data require confirmation in further studies.