38 Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, Presented at the After Intranasal Administration in Recreational Drug Users International Conference on Opioids (ICOO) 1 1 2 2 3 3 June 5 –7, 2016 Travis Mickle, Sven Guenther, Kathryn Roupe Jing Zhou , Daniel Dickerson , Lynn Webster Boston, Massachusetts 1KemPharm, Coralville, IA; 2Worldwide Clinical Trials, Austin, TX; 3PRA Health Sciences, Lenexa, KS Background • The treatments were single, equimolar, Results Figure 1. Mean Hydrocodone Plasma Levels After The proportions of subjects with various levels of E max Ease of Insufflation score was significantly higher (i.e., IN doses. separated by a washout period of Study-Drug Dosing (PK Population, N= 24) reduction (expressed as percent reduction from their E max more difficult) for IN benzhydrocodone than for IN HB, approximately 72 hours. for HB) are displayed in Figure 3 . Approximately 69% of at a mean (SD) VAS rating of 78.7 (20.0) vs 65.6 (26.3). Immediate-release opioids are commonly abused Study Participants. 66 subjects were enrolled. 40 The difference between least-squares mean values was via alternative routes such as intranasal (IN) and —Benzhydrocodone HCl, 13.34 mg • Cohort 1: ( n= 33) excluded from all PK analyses due to subjects showed some degree of reduction, approximately intravenous administration. 1 Benzhy drocodone n 43% showed a 30% reduction, approximately 29% showed 12.7 points (95% confidence interval: 19.4, 5.9; P=0.0004). blood sample mishandling. o —Hydrocodone bitartrate, 15.0 mg i t (also known as KP201) is a hydrocodone prodrug a a 50% reduct≥ion. Figure 4 shows Drug Liking over time r Safety. The overall incidence of treatment-emergent Pharmacokinetic Analyses. The primary • Cohort 2: ( n= 33) 24 subjects had evaluable pharma - t with inherent physicochemical and pharmaco - n 30 fo≥r IN benzhydrocodone and IN HB. cokinetic data (PK population). e adverse events (TEAEs) was similar across treatments, objective of the study was to compare the rate c logical properties designed to deter non-oral n at 30.8% after administration of benzhydrocodone and and extent of absorption of hydrocodone from • 54 subjects (28 from Cohort 1 and 26 from Cohort 2) were o C Figure 3. Responder Analyses Based on ) forms of abuse on a molecular level, rather than 27.8% after administration of HB. For both treatments, L benzhydrocodone relative to HB. randomized and received at least one dose of study drug a Percent Reduction in Drug Liking E max for IN m through formulation. Benzhydro codone is the m / s 20 the most commonly reported TEAEs were headache, g (safety population; 27 subjects per treatment sequence). a Benzhydrocodone Relative to IN HB (Completers l opioid active pharmaceutical ingredient in a novel, • For each treatment, plasma hydrocodone n P generalized pruritus, and nausea ( Table 2 ). No reported ( Population, N= 51) immediate-release hydrocodone combination concentration was assayed in blood samples • 51 subjects (94.4%) completed both treatment periods C TEAEs were classified as serious or severe. H TM (completer population). product (Apadaz ; see also poster #17). obtained pre-dose and at 0.083, 0.25, 0.5, 0.75, E 80 S ± 10 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose. Demographic and baseline characteristics of the safety Table 2. Treatment-Emergent Adverse Events n a a 70 (Safety Population) • Descriptive statistics were calculated for population and the PK population are summarized in e Objectives M ) Benzhydrocodone Hydrocodone Table 1. s parameters including peak plasma hydrocodone t Hydrochloride Bitartrate c 60 To compare the pharmacokinetics (PK) and abuse concentration (C ) and area under the plasma 0 e max j Adverse Event, n (%) 13.34 mg ( N= 52) 15.00 mg ( N= 54) potential of benzhydrocodone hydro chloride Table 1. Subjects’ Demographic and Baseline 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 b hydrocodone concentration-time curve from u Any 16 (30.8%) 15 (27.8%) S 50 Characteristics Time (hours) Headache 4 (7.7%) 4 (7.4%) with those of hydrocodone bitartrate (HB) time zero to 0.5 hours (AUC 0–0.5 ), 1 hour f o Safety Population PK Population Pruritus generalized 3 (5.8%) 3 (5.6%) following IN administration to non-dependent, (AUC 0–1 ), 2 hours (AUC 0–2 ), 4 hours (AUC 0–4 ), Characteristic (N= 54) (N= 24) Benzhydrocodone HB % 40 ( Nausea 2 (3.8%) 2 (3.7%) recreational opioid users. s 8 hours (AUC 0–8 ), and 24 hours (AUC 0–24 ). Age (years) Mean (SD) 27.7 (7.3) 27.5 (6.5) HB, hydrocodone bitartrate; HC, hydrocodone; PK, pharmacokinetics; SE, standard error. r Nasal congestion 1 (1.9%) 1 (1.9%) e Median [range] 26 [18–49] 26.5 [18–46] d 30 Vomiting 1 (1.9%) 1 (1.9%) • A linear mixed-effect model was used to analyze Sex, n (%) Male 41 (75.9%) 18 (75.0%) Figure 2. Ratios of Log-Transformed Geometric n o Dizziness 0 2 (3.7%) the natural log-transformed PK parameters Female 13 (2.1%) 6 (25.0%) p Methods Least-Squares Mean Values of Hydrocodone s 20 aThe listing includes all events reported in 3% of all subjects. Race, n (%) White 48 (88.9%) 20 (83.3%) e (C max and AUCs). The least square (LS) geo - Parameters for IN Benzhydrocodone and IN HB R This was a randomized, double-blind, two-way Black/African American 4 (7.4%) 2 (8.3%) ≥ metric mean ratio (test/control) along with the (PK Population, N= 24) crossover study. Other 2 (3.7%) 2 8.3%) 10 corresponding 90% confidence intervals (CI) Weight (kg) Mean (SD) 76.8 (14.6) 78.3 (15.4) **** Study Participants. Study participants included were calculated. Median [range] 71.2 [55.2–120.9] 72.6 [58.9–120.9] Cmax 0 Conclusions 2 experienced opioid users, male or female, 18 to BMI (kg/m ) Mean (SD) 25.0 (3.6) 25.3 (3.6) **** >0 ≥10% ≥20% ≥30% ≥40% ≥50% ≥60% ≥70% ≥80% ≥90% 100% Pharmacodynamic Analyses. At 0.25, 0.5, Median [range] 24.4 [19.4–32.8] 25.0 [19.5–32.8] AUC 0–0.083 • In recreational opioid abusers, IN benzhydro codone 55 years of age, inclusive, who were not currently Drug class most often abused during the past 12 weeks, n (%) **** Responder Criterion 1, 1.5, 2, 3, 4, 6, and 8 hours post-dose, each AUC 0–0.25 produced reductions in peak and cumulative physically dependent on opioids. Opioids/morphine derivatives 24 (44.4%) 12 (50.0%) (% Reduction in Drug Liking E max ) subject was asked, “Do you like the drug effect **** hydrocodone exposure compared with IN HB. Stimulants 16 (29.6%) 7 (29.2%) AUC 0–0.5 Emax , maximum Drug Liking, as rated by subjects on a 100-point, bipolar visual analogue scale anchored at 0 by “strong disliking ,” at 50 by “neither like nor Qualification Phases. Each part of the study you are feeling now?” Other 14 (25.9%) 5 (20.8%) **** dislike ,” and at 100 by “strong liking”; HB, hydrocodone bitartrate; IN, intranasal. AUC • Drug Liking data mirrored the PK findings, began with an in-clinic Qualification Phase • Subjects responded on a 100-point, bipolar Frequency of drug abuse 0–0.75 Total during the past 12 weeks **** Figure 4. Drug Liking Over Time for IN where lower early and peak exposure with consisting of a Naloxone Challenge (to confirm AUC 0–1 VAS anchored at 0 by “strong disliking,” at Mean (SD) 144.9 (219.0) 114.9 (219.2) 2 Benzhydrocodone and IN HB ( N= 51) benzhydrocodone was associated with lower the absence of physical opioid dependence) . 50 by “neither like nor dislike,” and at 100 by Median [range] 91 [3–1,036] 45 [6–1,017] **** AUC 0–2 Drug Liking early in the time course and with a • In contrast to most human abuse potential “strong liking.” IN during the past 12 months **** 100 Mean (SD) 54.5 (83.5) 36.0 (25.3) AUC 0–4 lower Drug Liking E max . studies, there was no drug discrimination test • At 5 minutes, each subject assessed the Median [range] 36 [5–570] 36.5 [6–100] **** and therefore the study was not enriched in AUC 0–6 • These differences in Drug Liking were observed Eas≤e of Insufflation (“snorting”). For this BMI, body mass index; IN, intranasal; PK, pharmacokinetics; SD, standard deviation. 90 subjects that could differentiate active drug **** despite lack of a Drug Discrimination Test typically rating, a 100-point, unipolar VAS was utilized, AUC 0–8 from placebo. As such, this design made it Pharmacokinetic Findings. For each treatment, **** g included to enrich the population with subjects n anchored at 0 by “very easy” and at 100 by AUC last i k 80 less likely to demonstrate differences in Drug hydrocodone plasma levels throughout the first four i that can differentiate active drug from placebo. **** L “very difficult.” Liking between the two treatments. post-dose hours are displayed in Figure 1. Ratios between AUC inf g u • In addition to descriptive statistics, parameters log-transformed geometric least-squares mean values of r • Benzhydrocodone was more difficult to insufflate D 70 Study Design. Following the naloxone challenge, 0 10 20 30 40 50 60 70 80 90 100 110 derived for Drug Liking VAS and Ease of selected pharmacokinetic parameters are displayed in E than HB. Ratio Between LSMs (%) ± 90% CI, Benzhydrocodone to HB S and a washout period of at least 12 hours: ± I nsufflation VAS were analyzed using a standard Figure 2.