Multiple Dose Pharmacokinetics of Tapentadol Oral Solution for the Treatment of Moderate to Severe Acute Pain in Children Aged 2 to <7 Years.

Background: This prospective, open-label trial was conducted to fulfil a post-approval commitment made to the competent authorities to extend the indication of the strong opioid analgesic tapentadol hydrochloride oral solution (OS) to the pediatric population. Patients and Methods: The trial assessed the pharmacokinetic (PK) profile of tapentadol, tapentadol-O-glucuronide and tapentadol-O-sulfate after administration of multiple doses of tapentadol OS (1.25 mg tapentadol/kg bodyweight every 4 h for up to 72 h) in children aged 2 to <7 years after a painful event that produces acute pain requiring treatment with a strong analgesic. The obtained PK data were integrated into a previously developed population PK (popPK) model based on single-dose data and then a model-based PK evaluation was performed. The primary trial endpoint was the area under the concentration-time curve at steady state for the dosing interval (AUCτ,ss) for tapentadol. Results: Ten children received tapentadol OS; all completed the trial. Multiple administrations of the trial medication resulted in tapentadol serum concentrations within the concentration range predicted by the previously developed popPK model. The estimated model-based AUCτ,ss values for tapentadol ranged from 142 to 321 h•ng/mL. They were within the predicted exposure range with no higher than expected accumulation for the employed dosing regimen and also within the targeted steady state exposure range observed in adults receiving multiple doses of immediate release tapentadol 50 to 100 mg. The treatment regimen was safe and well tolerated. Conclusion: The findings confirm the linear and predictable PK profile of tapentadol hydrochloride. The good agreement between the observed data and the model predictions shows the value of modelling and simulations in the planning and analysis of pediatric clinical trials and the ability to utilize the established PK models to predict multiple dose exposure.

Tapentadol for the Treatment of Moderate-to-Severe Acute Pain in Children Under the Age of Two Years.

BACKGROUND: Pharmacokinetics (PK), efficacy, and safety of the opioid analgesic tapentadol in the treatment of moderate-to-severe acute pain have so far not been investigated in pediatric patients <2 years of age. PATIENTS AND METHODS: Two multicenter, open-label trials assessed the pharmacokinetic profile, safety, tolerability, and efficacy of single doses of tapentadol oral solution (OS; NCT02221674; n=19) or intravenous infusion (IV, EudraCT 2014-002259-24; n=38) in children from birth to <2 years of age. Of these, 8 preterm neonates were included in the IV trial. A third randomized, double-blind, placebo-controlled trial (NCT02081391) investigated the efficacy and safety of multiple tapentadol OS doses in patients from birth to <2 years (placebo n=4, tapentadol n=11) using an immediate rescue trial design. Patients in all three trials underwent surgery that, in the investigator's opinion, reliably produced moderate-to-severe pain requiring opioid treatment. RESULTS: Administration of single tapentadol doses resulted in tapentadol serum concentrations within the targeted range known to be safe and efficacious in adults and compared well to the range observed for children aged 2 to <18 years. Pain intensity already improved 15 min after administration. In the multiple dose trial, amounts of supplemental opioid analgesic medication within the first 24 h after start of trial medication were low (placebo 0.02 mg/kg, tapentadol 0.05 mg/kg). All patients stopped treatment with the trial medication because opioid analgesics were no longer required. Treatment-emergent adverse events occurred in 42.1% (tapentadol OS single dose), 28.9% (tapentadol IV), and 75% of placebo and 54.5% of tapentadol patients (tapentadol OS multiple doses), none of them serious. CONCLUSION: Tapentadol showed a favorable PK and safety profile in children <2 years of age. Multiple tapentadol OS dosing is efficacious and generally well tolerated in children ≥2 years and might also be a useful treatment option for children <2 years in need of strong analgesics.

The challenge of developing pain medications for children: therapeutic needs and future perspectives.

It is broadly accepted that children of all age groups including (preterm) neonates and young infants can perceive pain and that there is an absolute need to treat their pain safely and effectively. The approved treatment options for children, particularly (preterm) neonates and young infants, are very limited with only a few medications specifically labelled for this population. This article presents the challenges of developing pain medications for children. A short overview gives information on pain in children, including pain perception, prevalence of pain and the long-term consequences of leaving pain untreated in this vulnerable population. Current pain management practices are briefly discussed. The challenges of conducting pediatric clinical trials in general and trials involving analgesic medications in particular within the regulatory framework available to develop these medications for children are presented. Emphasis is given to the operational hurdles faced in conducting a pediatric clinical trial program. Some suggestions to overcome these hurdles are provided based on our experience during the pediatric trial program for the strong analgesic tapentadol used for the treatment of moderate to severe acute pain.

Efficacy and safety of multiple doses of tapentadol oral solution in the treatment of moderate to severe acute pain in children aged 2 to <18 years - a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Well-controlled trials of analgesics in the pediatric population are scarce. Tapentadol is a strong centrally acting analgesic which has undergone a pediatric development program investigating its suitability for treating moderate to severe acute pain across the entire pediatric age range from birth to adolescence. Here, we report data from a pivotal Phase III trial performed as part of this development program. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled, multicenter clinical trial investigated efficacy and safety/tolerability of multiple tapentadol oral solution doses (OS; target dose 1.25 mg/kg) in the treatment of postsurgical acute pain. Data for patients aged 2 to <18 years are reported here. The main objective of the trial was to investigate if oral tapentadol administration compared to placebo reduces the use of supplemental opioid analgesic medication within the first 24 hrs of treatment. Other investigated parameters included taste and palatability of the trial medication, adverse events (AEs), vital signs, and laboratory parameters. RESULTS: A total of 160 patients were included (placebo n=52, tapentadol n=108). It was shown that the total amount of supplemental opioid analgesic medication used in the first 24 hrs was significantly lower in tapentadol patients than placebo patients (p=0.0154). Taste and palatability of tapentadol OS was well perceived by most patients. Treatment-emergent AEs were reported in 50% of patients treated with placebo vs 57.4% in those exposed to tapentadol, most commonly vomiting, nausea, and constipation in both treatment groups. CONCLUSION: Tapentadol OS was effective and generally well tolerated in children (≥2 years) for the treatment of moderate to severe acute pain. Across all age groups, palatability and acceptability of tapentadol OS were sufficient to ensure intake compliance. This trial provides evidence that tapentadol OS can be effectively used to treat pain in young patients for whom currently limited labelled treatment options are available.

S. pombe CLASP needs dynein, not EB1 or CLIP170, to induce microtubule instability and slows polymerization rates at cell tips in a dynein-dependent manner.

The Schizosaccharomyces pombe CLIP170-associated protein (CLASP) Peg1 was identified in a screen for mutants with spindle formation defects and a screen for molecules that antagonized EB1 function. The conditional peg1.1 mutant enabled us to identify key features of Peg1 function. First, Peg1 was required to form a spindle and astral microtubules, yet destabilized interphase microtubules. Second, Peg1 was required to slow the polymerization rate of interphase microtubules that establish end-on contact with the cortex at cell tips. Third, Peg1 antagonized the action of S. pombe CLIP170 (Tip1) and EB1 (Mal3). Fourth, although Peg1 resembled higher eukaryotic CLASPs by physically associating with both Mal3 and Tip1, neither Tip1 nor Mal3 was required for Peg1 to destabilize interphase microtubules or for it to associate with microtubules. Conversely, neither Mal3 nor Tip1 required Peg1 to associate with microtubules or cell tips. Consistently, while mal3.Delta and tip1.Delta disrupted linear growth, corrupting peg1 (+) did not. Fifth, peg1.1 phenotypes resembled those arising from deletion of the single heavy or both light chains of fission yeast dynein. Furthermore, all interphase phenotypes arising from peg1 (+) manipulation relied on dynein function. Thus, the impact of S. pombe CLASP on interphase microtubule behavior is more closely aligned to dynein than EB1 or CLIP170.

Fta2, an essential fission yeast kinetochore component, interacts closely with the conserved Mal2 protein.

The fission yeast multiprotein-component Sim4 complex plays a fundamental role in the assembly of a functional kinetochore. It affects centromere association of the histone H3 variant CENP-A as well as kinetochore association of the DASH complex. Here, multicopy suppressor analysis of a mutant version of the Sim4 complex component Mal2 identified the essential Fta2 kinetochore protein, which is required for bipolar chromosome attachment. Kinetochore localization of Mal2 and Fta2 depends on each other, and overexpression of one protein can rescue the phenotype of the mutant version of the other protein. fta2 mal2 double mutants were inviable, implying that the two proteins have an overlapping function. This close interaction with Fta2 is not shared by other Sim4 complex components, indicating the existence of functional subgroups within this complex. The Sim4 complex seems to be assembled in a hierarchical way, because Fta2 is localized correctly in a sim4 mutant. However, Fta2 kinetochore localization is reduced in a spc7 mutant. Spc7, a suppressor of the EB1 family member Mal3, is part of the conserved Ndc80-MIND-Spc7 kinetochore complex.

The fission yeast kinetochore component Spc7 associates with the EB1 family member Mal3 and is required for kinetochore-spindle association.

A critical aspect of mitosis is the interaction of the kinetochore with spindle microtubules. Fission yeast Mal3 is a member of the EB1 family of microtubule plus-end binding proteins, which have been implicated in this process. However, the Mal3 interaction partner at the kinetochore had not been identified. Here, we show that the mal3 mutant phenotype can be suppressed by the presence of extra Spc7, an essential kinetochore protein associated with the central centromere region. Mal3 and Spc7 interact physically as both proteins can be coimmunoprecipitated. Overexpression of a Spc7 variant severely compromises kinetochore-microtubule interaction, indicating that the Spc7 protein plays a role in this process. Spc7 function seems to be conserved because, Spc105, a Saccharomyces cerevisiae homolog of Spc7, identified by mass spectrometry as a component of the conserved Ndc80 complex, can rescue mal3 mutant strains.