Quantification of the analgesic effect of intranasal coadministration of ketamine and sufentanil in adults to support the development of a pain relief treatment (CT001) in children
Rik Schoemaker(1), Mads Werner(2), Martin Juhl(3)
(1) Occams, Amstelveen, Netherlands, (2) Multidisciplinary Pain Center, Neuroscience Center, Copenhagen University Hospitals - Rigshospitalet, København, Denmark, (3) Cessatech A/S, København, Denmark
Introduction/Objectives: In the development program for a non-invasive treatment for acute and procedural pain in children, intranasal coadministration of sufentanil (S) and ketamine (K) is investigated, where K is known for its opioid-sparing effect. A dose combination has been established in clinical (off-label) practice. For formal registration of the combination treatment (CT001), support is required to confirm the posology in children. As placebo-controlled pain studies are unethical in children, a trial in adults was performed after third molar extraction.
Methods: Four dose levels of K (0, 13, 27, and 40mgK) were combined with four dose levels of S (0, 13, 27, and 40µgS), resulting in 16 combinations where the four main treatment arms (combinations of 0 and 27mgK, and 0 and 27µgS) had 40 subjects each, and the additional 12 combinations had 5 subjects each. Two doses at each level were given 1 hour apart. Both PK was sampled and a numerical rating scale for pain (NRS) was assessed over 3 hours.
S and K pharmacokinetic (PK) models were developed, combining the PK data from 4 studies: the present pain study, combined with PK data from a separate bioavailability study in 12 healthy subjects and two paediatric PK studies with 37 children from 1 to 17 years [1].
The NRS pain model described the natural progression of pain over time, the effects of S and K concentration, and their interaction.
On the assumption that the effect CT001 on NRS is the same for adults and children, simulations were performed to investigate the effect of dose modifications of the proposed posology in children and the effect of a second dose after 15 minutes when efficacy of the first dose was insufficient.
Results: PK profiles were well-described using two-compartment models with combined first- and zero-order absorption and individual empirical Bayes estimates were used to drive the pain model. Clearance and volume parameters were scaled using fixed allometric constants [2], and a pronounced effect of age on bioavailability was estimated using a sigmoid Emax model, analogous to a derived relationship between surface area of the nose per kg body weight across the age range [3].
The NRS pain model comprised a baseline pain score, an Emax over time component for natural pain progression, a sigmoid Emax effect of S effect compartment concentration, an Emax effect of K plasma concentration, and a log-linear relationship between K concentration and EC50 quantifying 50% of the maximum effect of S on NRS. All components were added, and NRS pain scores were analysed after a logit transform to ensure not exceeding the 0-10 range.
All model components were highly significant with S as the most potent compound. The combination treatment was found to be superior to either S or K alone at the same concentrations.
The simulated pain reduction in NRS in children using the proposed posology was 87% (76%/92%) with a 95% CI for n=37. Corresponding values with only S exposure were 52% (34%/65%) and only K exposure were 32% (12%/47%), with a 10% (1%/20%) increase for placebo. Increasing CT001 exposure in children would lead to only small increases in pain reduction, while decreases in exposure would result in insufficient effects.
The pain relief estimated for CT001 would be difficult to obtain with S alone in children and would likely require more than double the S exposure while increasing S or K exposure could lead to side-effects like respiratory depression or hallucinogenic effects. Only 9% of children are expected to require a second dose of CT001.
The following algorithm may be used to select the dose for children based on body weight: <15kg: 6mgK+6µgS, 15-<20kg: 9mgK+9µgS, 20-<30kg: 12mgK+12µgS, 30-<45kg: 18mgK+18µgS, ≥45kg: 27mgK+27µgS, with an extra dose identical to the first dose at 15 min when pain relief is insufficient. A responder is classified as having >30% decrease in NRS or NRS ≤3 at 30 min, and >75% responders was considered acceptable. The % predicted responders was 90% for <15kg, 93% for 15-<20kg, 87% for 20-<30kg, 85% for 30-<45kg, and 79% for ≥45kg.
Conclusions: The proposed posology of CT001 in children is expected to provide adequate pain relief, and changes in exposure of either K or S are not suggested to lead to an improved efficacy profile. The decrease in EC50 of S with K exposure quantifies and confirms the benefits of the combination. The registration of CT001 as a safe and efficacious non-invasive treatment will likely improve the clinical management of pain in children.
References:
[1] Nielsen BN, Friis SM, Romsing J, Schmiegelow K, Anderson BJ, Ferreiros N, Labocha S, Henneberg SW. Intranasal sufentanil/ketamine analgesia in children. Paediatr Anaesth. 2014;24(2):170-80. doi: 10.1111/pan.12268 [doi].
[2] Anderson BJ and Holford NHG. Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol (2008) 48:303-332
[3] T. Ertekin, M. Değermenci, M. Nisari, E. Unur, A. Coşkun. Age-related changes of nasal cavity and conchae volumes and volume fractions in children: a stereological study. Folia Morphol., 2016, Vol. 75, No. 1. pp. 38–47.
