Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis

Abstract

Abstract:The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed-effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1-2 and three times higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25-mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit.

Effect of bupivacaine lozenges on oral mucositis pain: a randomized controlled multicenter phase II study

“…Method and results of these data on the 10 patients are reported in the study by Mogensen et al, 2017. 10 …”

“…They showed no signs of toxic plasma concentrations or risk of aspiration. 10 , 11 Moreover, a pilot study in which a single dose of the lozenge was administered to patients with head and neck cancer showed a strong, long-lasting pain-relieving effect, with a mean duration of maximum pain relief in the oral cavity of 42 minutes and a significant pain relief even after 180 minutes. 12 Lidocaine viscous solution has been reported to have a duration of 15 to 20 minutes.…”

Effects of medicines used to treat gastrointestinal diseases on the pharmacokinetics of coadministered drugs: a PEARRL Review

“…Oral mucositis is a side effect of azathioprine therapy . In patients with oral mucositis, bupivacaine absorption from lozenges was increased and a trend to higher fentanyl absorption administered with a sublingual spray was observed but did not reach statistical significance . The effect may be due to impairment of the barrier function of the mucosa.…”

A novel lozenge containing bupivacaine as topical alleviation of oral mucositis pain in patients with head and neck cancer: a pilot study

“…In these studies, absorption of bupivacaine and the risk of aspiration were investigated and no toxic plasma concentrations or signs of aspiration were observed, whereas the results indicated that a bupivacaine lozenge is safe to use. 14 , 15…”