(M0930-10-55) Vocacapsaicin (formerly CA-008): A Water-Soluble Prodrug for Rapid Release of Capsaicin for the Treatment of Post-Surgical Pain

Purpose: Safe and effective management of pain during the initial weeks after surgery remains a significant unmet medical need.^1,2 The ideal analgesic for post-operative pain management is locally delivered into the surgical site, is devoid of systemic toxicity, and provides long-lasting pain relief without muscle weakness.³
Capsaicin, a known TRPV1 agonist, selectively defunctionalizes TRPV1 expressing C-fiber nociceptors to provide long-lasting analgesia without impacting motor function.⁴ Capsaicin, however, has low ( < 0.1 mg/mL⁵) water solubility which limits safe and effective administration into the surgical site. Vocacapsaicin is an acid-stable prodrug of capsaicin that is readily administered to surgical site(s) by local infiltration. With a water-solubility of >50 mg/mL, vocacapsaicin is greater than 100-fold more soluble than capsaicin. At physiologic pH, vocacapsaicin rapidly releases capsaicin and CA-101 concurrently via an intra-molecular, cyclization-release mechanism (Figure 1). Studies presented below demonstrate that vocacapsaicin efficiently converts to capsaicin both in vitro and in vivo as intended and enables rapid and efficient delivery of capsaicin.

Methods: The in vitro rate of conversion of vocacapsaicin to capsaicin and CA-101 was assessed under physiologic-simulating conditions, pH 7.5 and 37˚C (0.2 mg/mL in phosphate buffer) using RP-UPLC. In addition, a moderately acidic solution of vocacapsaicin (pH 3.9 citrate buffer in saline; 0.15 mg/mL) was evaluated for formulation stability. In vivo, the pharmacokinetics (PK) after administration of vocacapsaicin was determined and compared to that of direct administration of capsaicin. Pharmacokinetics were determined in Sprague Dawley rats (N= 5 per treatment group) where vocacapsaicin (1.62 mg/kg vocacapsaicin HCl in saline, 0.4 mg/mL, pH 5.4) or capsaicin (1 mg/kg, 0.25 mg/mL in 25% PEG300/sterile water) was administered as equimolar (3.27 µmole/kg) subcutaneous (SC) doses. An LC-MS/MS method was used for the quantification of vocacapsaicin, capsaicin, and CA-101 in rat plasma. Blood was collected into K2-EDTA tubes containing citrate buffer (pH 3) to stabilize intact prodrug present upon blood collection. Noncompartmental PK parameters were calculated with Phoenix WinNonlin.

Results: In vitro, vocacapsaicin at pH 7.5, 37˚C quantitatively converts to capsaicin and CA-101 rapidly with a half-life of about 3 minutes. At lower pH and temperature (pH 3.9, ambient temperature) the compound is essentially unchanged over several hours ( < 2% loss in 4 hours). In vivo, the time-concentration curve of capsaicin in rats was similar following equimolar doses of vocacapsaicin or capsaicin (Figure 2). Capsaicin AUC_0-t following prodrug administration was 163 ± 28 ng·hr/mL compared to 155 ± 20 ng·hr/mL following administration of capsaicin alone. Likewise, the capsaicin C_max following vocacapsaicin administration was 89.7 ± 33.3 ng/mL compared to 81.1 ± 22.7 ng/mL following administration from capsaicin alone. Plasma levels of vocacapsaicin fell quickly and were orders of magnitude less than capsaicin (C_max = 10.4 ± 10.6 ng/mL; T_max = 0.06 ± 0.06 h; AUC_0-t = 1.41 ± 0.96 ng·hr/mL). The profile of CA-101 (C_max = 121 ± 17 ng/mL; T_max = 1.2 ± 0.45 h; AUC_0-t = 397 ± 46 ng·hr/mL) suggests that CA-101 is also rapidly released from vocacapsaicin after administration.

Conclusion: Vocacapsaicin is being developed as a novel, water-soluble prodrug that allows for infiltration into surgical sites. In vivo observations in rats are consistent with the rapid conversion to capsaicin measured in vitro at physiologic-simulating conditions. In rats, vocacapsaicin converts efficiently, providing capsaicin exposure comparable to equimolar capsaicin administration. Vocacapsaicin was also shown to be stable in moderately acidic solutions, allowing for dose formulation preparation without complex excipients.
This work, along with data showing clinical efficacy in patients following total knee arthroplasty, bunionectomy, and ventral hernia repair^6,7,8, demonstrates that vocacapsaicin allows for efficient delivery of capsaicin, a TRPV1 agonist, to the surgical site. Vocacapsaicin is currently in Phase 3 clinical development for the treatment of postsurgical pain.

References: 1) Price AJ, Alvand A, Troelsen A, et al. Knee replacement. Lancet 2018;392(10158):1672-1682.
2) Chan EY, Blyth FM, Nairn L, Fransen M. Acute postoperative pain following hospital discharge after total knee arthroplasty. Osteoarthritis Cartilage 2013;21(9):1257-1263.
3) Hamilton TW, Knight R, Stokes JR, et al. Efficacy of liposomal bupivacaine and bupivacaine hydrochloride vs bupivacaine hydrochloride alone as a periarticular anesthetic for patients undergoing knee replacement: a randomized clinical trial. JAMA Surg. Published online April 06, 2022. doi:10.1001/jamasurg.2022.0713
4) Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998;21(3):531-43
5) The Hazardous Substances Data Bank (HSDB), Capsaicin; U.S. Department of Health and Human Services, National Institutes of Health, National Library of Medicine: Bethesda, MD, 2006.
6) Teichman S, Leiman D, Minkowitz H, et al. Vocacapsaicin reduces pain and opioid consumption for two weeks following a single ad- ministration during total knee arthroplasty. Poster presented at: 46th Annual Regional Anesthesiology and Acute Pain Meeting; May 13–15, 2021; Lake Buena Vista, FL
7) Gottlieb IJ, Beaton A, Solanki D, et al. A randomized placebo‐ controlled trial of intraoperative administration of CA‐008 for post‐ operative analgesia following bunionectomy. Poster presented at: 44th Annual Regional Anesthesiology and Acute Pain Meeting; April 11–13, 2019; Las Vegas, NV.
8) Teichman S, Minkowitz H, Leiman D, et al. Pilot study of vocacapsaicin for treatment of pain following open laparotomy repair of ventral hernia. Poster presented at: 47th Annual Regional Anesthesiology and Acute Pain Meeting; March 31 – April 2, 2022; Las Vegas, NV


Mechanism of release of capsaicin and CA-101 from vocacapsaicin


Exposures of capsaicin following SC administration of equimolar vocacapsaicin and capsaicin in Rat; CA-101 and prodrug exposures also shown for vocacapsaicin treated rats