Search

Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK‐positive non‐small cell lung cancer, is being assessed in children with ALK‐positive solid and central nervous system tumors. An ad hoc pediatric‐friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high‐fat meal and seven receiving low‐fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration–time curve extrapolated to infinity (AUC0‐∞) and 3.0 for maximum observed concentration (Cmax) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0‐∞ following a high‐fat meal versus fasted conditions (GMR 1.7 [90% confidence interval 1.4–2.2]). Alectinib AUC0‐∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule. [ABSTRACT FROM AUTHOR]

Aim: This phase I, multicentre, open‐label, nonrandomised, parallel‐group, two‐part study aimed to evaluate the effect of mild to moderate hepatic impairment on the pharmacokinetics (PK), safety and tolerability of a single oral dose of risdiplam. Methods: Adult subjects (aged 18‐70 years) with mild (Child‐Pugh Class A; Part 1) or moderate (Child‐Pugh Class B; Part 2) hepatic impairment were matched with subjects with normal hepatic function on sex, age, body mass index and smoking status. Each subject received a single oral dose of 5 mg of risdiplam. Plasma concentrations of risdiplam and its metabolite M1 were measured and PK parameters were compared. Adverse events, laboratory abnormalities, vital signs and electrocardiogram measurements were assessed. Results: After a single dose (5 mg) of risdiplam, the risdiplam PK parameters area under the plasma concentration‐time curve from time zero to infinity and maximum observed plasma concentration were approximately 20% and 5% lower, respectively, in subjects with mild hepatic impairment and approximately 8% and 20% higher, respectively, in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. These differences were not statistically significant; all 90% confidence intervals for geometric least squares‐means ratios spanned unity. No new risdiplam‐related safety findings were observed in subjects with mild or moderate hepatic impairment. Conclusion: Mild or moderate hepatic impairment did not have a clinically relevant impact on the PK of risdiplam. Therefore, no dose adjustment is required in patients with mild or moderate hepatic impairment when receiving risdiplam. [ABSTRACT FROM AUTHOR]

Risdiplam (Evrysdi) improves motor neuron function in patients with spinal muscular atrophy (SMA) and has been approved for the treatment of patients ≥2 months old. Risdiplam exhibits time‐dependent inhibition of cytochrome P450 (CYP) 3A in vitro. While many pediatric patients receive risdiplam, a drug–drug interaction (DDI) study in pediatric patients with SMA was not feasible. Therefore, a novel physiologically‐based pharmacokinetic (PBPK) model‐based strategy was proposed to extrapolate DDI risk from healthy adults to children with SMA in an iterative manner. A clinical DDI study was performed in healthy adults at relevant risdiplam exposures observed in children. Risdiplam caused an 1.11‐fold increase in the ratio of midazolam area under the curve with and without risdiplam (AUCR)), suggesting an 18‐fold lower in vivo CYP3A inactivation constant compared with the in vitro value. A pediatric PBPK model for risdiplam was validated with independent data and combined with a validated midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric patients with SMA. The impact of selected intestinal and hepatic CYP3A ontogenies on the DDI susceptibility in children relative to adults was investigated. The PBPK analysis suggests that primary CYP3A inhibition by risdiplam occurs in the intestine rather than the liver. The PBPK‐predicted risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 2 months–18 years was negligible (midazolam AUCR of 1.09–1.18) and included in the US prescribing information of risdiplam. Comprehensive evaluation of the sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A ontogeny functions, together with PBPK model‐based strategy proposed here, aim to guide and facilitate DDI extrapolations in pediatric populations. [ABSTRACT FROM AUTHOR]

Aims: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry‐into‐human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers. Methods: Part 1 had a randomized, double‐blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6–18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two‐period cross‐over design (n = 8). Results: Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi‐phasic decline with a mean terminal half‐life of 40–69 h. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27–55%) of the estimated maximum increase in SMN2 mRNA. Conclusions: Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full‐length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues. [ABSTRACT FROM AUTHOR]

ABSTRACT The synthetic peptide drug taspoglutide, developed for treatment of diabetes, must be quantified at low pg/mL levels in biological samples. This manuscript describes the improvement of a previous method, featuring orthogonal hydrophilic interaction to reversed-phase chromatography column switching and tandem mass spectrometric detection. Signal-to-noise ratio was enhanced and isobaric interferences were reduced by ultra-performance separation using a basic mobile phase in 'wrong-way-round' ionization mode and monitoring a selective fragment ion. Tedious solid-phase extraction cleanup was abandoned in favor of simple protein precipitation. Urine required the addition of surfactants to prevent adsorptive drug loss. Dissociation of complexes with possibly formed anti-drug antibodies was achieved with formic acid. Lower limits of quantitation (LLOQ) were 4 pg/mL in human plasma and 10 pg/mL in urine using a 250 μL sample, and an LLOQ of 50 pg/mL was obtained in animal plasma using 50 μL. Precision, accuracy and incurred samples reproducibility fulfilled regulatory requirements. Simultaneous determination of unlabeled and stable isotope labeled taspoglutide, interesting for clearance studies in which both compounds are co-administered, was realized using a structural analog as internal standard. The described method offered excellent sensitivity with low sample consumption, reasonable throughput, moderate costs and high robustness for routine analysis. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]