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Opioids are the primary drugs used in Western medicine for pain management and palliative care. Farming of opium poppies remains the sole source of these essential medicines, despite diverse market demands and uncertainty in crop yields due to weather, climate change, and pests. We engineered yeast to produce the selected opioid compounds thebaine and hydrocodone starting from sugar. All work was conducted in a laboratory that is permitted and secured for work with controlled substances. We combined enzyme discovery, enzyme engineering, and pathway and strain optimization to realize full opiate biosynthesis in yeast. The resulting opioid biosynthesis strains required the expression of 21 (thebaine) and 23 (hydrocodone) enzyme activities from plants, mammals, bacteria, and yeast itself. This is a proof of principle, and major hurdles remain before optimization and scale-up could be achieved. Open discussions of options for governing this technology are also needed in order to responsibly realize alternative supplies for these medically relevant compounds.

Background and Objective A hydrocodone extended-release (ER) formulation employing the CIMA ® Abuse-Deterrence Technology platform was developed to provide resistance against rapid release of hydrocodone when tablets are comminuted or taken with alcohol. This study evaluated the pharmacokinetics of three hydrocodone ER tablet prototypes with varying levels of polymer coating to identify the prototype expected to have the greatest abuse deterrence potential based on pharmacokinetic characteristics that maintain systemic exposure to hydrocodone comparable to that of a commercially available hydrocodone immediate-release (IR) product. Methods In this four-period crossover study, healthy subjects aged 18–45 years were randomized to receive a single intact, oral 45-mg tablet of one of three hydrocodone ER prototypes (low-, intermediate-, or high-level coating) or an intact, oral tablet of hydrocodone IR/acetaminophen (APAP) 10/325 mg every 6 h until four tablets were administered, with each of the four treatments administered once over the four study periods. Dosing periods were separated by a minimum 5-day washout. Naltrexone 50 mg was administered to block opioid receptors. Blood samples for pharmacokinetic assessments were collected predose and through 72 h postdose. Parameters assessed included maximum observed plasma hydrocodone concentration ( C max ), time to C max ( t max ), and area under the concentration-time curve from time 0 to infinity (AUC 0–∞ ). Results Mean C max values were 49.2, 32.6, and 28.4 ng/mL for the low-, intermediate-, and high-level coating hydrocodone ER tablet prototypes, respectively, and 37.3 ng/mL for the hydrocodone IR/APAP tablet; respective median t max values were 5.9, 8.0, 8.0, and 1.0 h. Total systemic exposure to hydrocodone (AUC 0–∞ ) was comparable between hydrocodone ER tablet prototypes (640, 600, and 578 ng·h/mL, respectively) and hydrocodone IR/APAP (581 ng·h/mL). No serious adverse events or deaths were reported. The most common adverse events included headache (26 %) and nausea (18 %). Conclusion All three hydrocodone ER tablet prototypes (low-, intermediate-, and high-level polymer coating) demonstrated ER pharmacokinetic characteristics. The hydrocodone ER tablet prototype with the high-level coating was selected for development because of its comparable exposure to the hydrocodone IR/APAP formulation and potentially increased ability to resist rapid drug release upon product tampering because of a higher polymer coating level. All study medications were well tolerated in healthy naltrexone-blocked volunteers.

AbstractBackgroundThe NaV1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV1.8, on control of acute pain is being studied.MethodsAfter establishing the selectivity of VX-548 for NaV1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo.ResultsA total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548.ConclusionsAs compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.)

The isomerization of neopinone to codeinone is a critical step in the biosynthesis of opiate alkaloids in opium poppy. Previously assumed to be spontaneous, the process is in fact catalyzed enzymatically by neopinone isomerase (NISO). Without NISO the primary metabolic products in the plant, in engineered microbes and in vitro are neopine and neomorphine, which are structural isomers of codeine and morphine, respectively. Inclusion of NISO in yeast strains engineered to convert thebaine to natural or semisynthetic opiates dramatically enhances formation of the desired products at the expense of neopine and neomorphine accumulation. Along with thebaine synthase, NISO is the second member of the pathogenesis-related 10 (PR10) protein family recently implicated in the enzymatic catalysis of a presumed spontaneous conversion in morphine biosynthesis. Neopinone isomerase catalyzes the isomerization of the opiate alkaloid neopinone to codeinone, driving the biosynthesis of codeine and morphine and preventing accumulation of their isomers neopine and neomorphine.

Metabolic engineering of yeast to incorporate plant and bacterial enzymes that construct and decorate morphine, along with spatial engineering to enable a spontaneous chemical reaction, provides strains capable of producing up to 130 mg/l of opioids. Opiates and related molecules are medically essential, but their production via field cultivation of opium poppy Papaver somniferum leads to supply inefficiencies and insecurity. As an alternative production strategy, we developed baker's yeast Saccharomyces cerevisiae as a microbial host for the transformation of opiates. Yeast strains engineered to express heterologous genes from P. somniferum and bacterium Pseudomonas putida M10 convert thebaine to codeine, morphine, hydromorphone, hydrocodone and oxycodone. We discovered a new biosynthetic branch to neopine and neomorphine, which diverted pathway flux from morphine and other target products. We optimized strain titer and specificity by titrating gene copy number, enhancing cosubstrate supply, applying a spatial engineering strategy and performing high-density fermentation, which resulted in total opioid titers up to 131 mg/l. This work is an important step toward total biosynthesis of valuable benzylisoquinoline alkaloid drug molecules and demonstrates the potential for developing a sustainable and secure yeast biomanufacturing platform for opioids.

A single-entity, once-daily, extended-release formulation of hydrocodone bitartrate (HYD) has been developed for the management of moderate to severe chronic pain. Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. CYP3A4 yields norhydrocodone, a major inactive metabolite, whereas CYP2D6 yields hydromorphone, a minor active metabolite. This study examined the influence of the coadministration of paroxetine, a strong selective CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone (and hydromorphone) in healthy adults. In this randomized, double-blind, 2-period, 2-treatment crossover study, 24 healthy subjects received paroxetine 20 mg or placebo once daily for 12 days and an HYD 20-mg tablet on day 10 of each period. Hydrocodone mean Cmax and t½ and median Tmax values were similar with paroxetine or placebo coadministration (16.8 vs 15.9 ng/mL, 8.5 vs 8.4 hours, and 18.0 vs 18.0 hours, respectively), as were mean AUC0–t and AUC0–∞ values (342.9 vs 325.3 ng · h/mL and 346.3 vs 328.5 ng · h/mL). The 90% CIs of the geometric mean ratios of the hydrocodone AUC and Cmax values were fully within the predetermined range of 80% to 125%, suggesting that there was no effect of multiple doses of paroxetine on systemic exposure to hydrocodone. Mean hydromorphone AUC0–t and Cmax values were decreased with paroxetine versus placebo (0.64 vs 3.8 ng · h/mL and 0.06 vs 0.19 ng/mL), whereas Tmax values remained similar (18.0 vs 16.1 hours, respectively). The mean hydromorphone AUC0–∞ value could not be calculated. Both regimens were well tolerated; after HYD administration, the numbers of adverse events were similar between the 2 treatment regimens, and all adverse events were mild. In this study, the coadministration of single-dose HYD with paroxetine at steady state did not alter systemic exposure to hydrocodone, suggesting that HYD can be coadministered with CYP2D6 inhibitors at therapeutic doses, without dosage modification.

A hydrocodone extended-release (ER) formulation was developed to provide sustained pain relief with twice-daily dosing. Developed using the CIMA abuse-deterrence technology platform (CIMA Labs Inc, Brooklyn Park, Minnesota), this formulation also provides resistance against rapid release of hydrocodone when tablets are comminuted and resistance against dose dumping when tablets are taken with alcohol. Two open-label studies evaluated hydrocodone ER pharmacokinetics (PK) after single- and multiple-dose administration in healthy, naltrexone-blocked subjects. In the single-dose period of both studies, healthy subjects aged 18 to 45 years of age received hydrocodone ER (study 1, 45 mg; study 2, 90 mg). In the multiple-dose period of study 1, subjects received one 45-mg hydrocodone ER tablet twice daily from the morning of day 1 through the morning of day 6. In the multiple-dose period of study 2, subjects received hydrocodone ER twice daily, titrated to 90 mg over 10 days (days 1 and 2, 45 mg; days 3 and 4, 60 mg; days 5–10, 90 mg). All subjects received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose in the single-dose period and after the final dose in the multiple-dose period. PK measures included maximum observed plasma drug concentration (Cmax), area under the plasma drug concentration by time curve from time 0 to the time of the last measurable drug concentration (AUC0–t), time to Cmax (Tmax), observed accumulation ratio (Robs), and steady-state plasma concentration (Css). Safety and tolerability were assessed. The PK analyses included 36 subjects from study 1 and 33 from study 2. Plasma hydrocodone PK parameters after single- and multiple-dose administration of hydrocodone ER 45 mg (study 1) were dose-normalized to 90 mg and pooled with data from study 2. As expected, Cmax was higher (125.4 vs 57.2 ng/mL), AUC0–t was higher (2561 vs 1095 ng·h/mL), and Tmax occurred earlier (5.0 vs 8.0 hours) with multiple-dose administration. Mean Robs after multiple-dose administration of hydrocodone ER was also slightly higher than predicted from single-dose data (2.8 vs 2.4). Css were achieved within 5 days of twice-daily administration of both doses. Mean fluctuation with hydrocodone ER 45 or 90 mg was 36.4% and 33.9%, respectively, and mean swing was 46.9% and 43.5%, respectively. The incidence of adverse events was similar in the single-dose (33%) and multiple-dose (29%) periods in study 1 and slightly higher in the multiple-dose (76%) than in the single-dose (53%) period in study 2. The PK profile of hydrocodone ER was qualitatively similar after single- and multiple-dose administration. The steady-state profile demonstrated sustained exposure with limited swing and fluctuation. Single and multiple doses of hydrocodone ER (45 and 90 mg) were generally well tolerated in healthy subjects receiving naltrexone; however, exposure to naltrexone may have confounded the interpretation of safety findings.

Background Greater drug content requirements for extended-release (ER) opioids necessitate greater protection against dose dumping. Hydrocodone ER employs the CIMA ® Abuse-Deterrence Technology platform, which provides resistance against rapid release of the active moiety when the tablet is manipulated or taken with alcohol. Objective Assess effects of alcohol on hydrocodone ER pharmacokinetics. Study Design Open-label, crossover (January 25–April 30, 2010). Setting Single center. Participants Forty healthy adults. Intervention Subjects received all four treatments in a randomized manner (separated by a minimum 5-day washout): hydrocodone ER 15 mg with 240 mL water and 240 mL orange juice containing 4, 20, and 40 % alcohol in a fasted state. Naltrexone was administered to minimize opioid-related adverse events. Main Outcome Measure Effect of alcohol on pharmacokinetics of hydrocodone ER assessed by comparing systemic exposure [maximum plasma drug concentration ( C max ) and area under the plasma drug concentration-versus-time curve from time 0 to infinity (AUC 0–∞ )] after administration with alcohol or with water. Results Geometric means ratios of hydrocodone ER with 4, 20, and 40 % alcohol relative to water were 1.05, 1.09, and 1.14, respectively, for C max and 1.07, 1.13, and 1.17, respectively, for AUC 0–∞ . All 90 % confidence intervals for these geometric means ratios fell within the limits of 0.8 and 1.25. Increasing alcohol concentrations did not notably affect systemic exposure but were associated with increased adverse events. Conclusions Hydrocodone ER tablets were resistant to dose dumping when administered with alcohol in healthy subjects based on similar systemic exposures observed across all treatments.

We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.

The Na 1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na 1.8, on control of acute pain is being studied. After establishing the selectivity of VX-548 for Na 1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).