Clinical evaluation of the first oxycodone once daily prolonged release tablet in moderate to severe chronic pain: a randomized, double-blind, multicenter, cross-over, non-inferiority study to investigate efficacy and safety in comparison with an established oxycodone twice daily prolonged release tablet

Lux, Eberhard A.; Janecki, Marcin; Maritz, Martina Alice

doi:10.1185/03007995.2014.946126

Cited by 9 publications

(4 citation statements)

References 33 publications

(35 reference statements)

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“…It could be assumed that OOD leads to comparable efficacy and safety and is therefore exchangeable when administered at the same total daily dose as OTD. This finding could be confirmed by results of a recent trial in patients [ 28 ]. The randomized, double-blind, cross-over trial in patients with malignant and nonmalignant moderate to severe chronic pain showed that OOD is at least equivalent to OTD regarding therapeutic efficacy and safety.…”

Section: Discussionsupporting

confidence: 75%

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet

Scheidel¹,

Maritz²,

Gschwind³

et al. 2017

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Objective: To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Materials and methods: Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Results: Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (Cmax), and plasma concentrations at the end of the dosing interval (Cτ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80.00 – 125.00%. Bioavailability of OOD was not influenced by concomitant food intake. OOD and OTD were generally well tolerated, a difference between the two products could not be observed. Conclusion: The new 10-mg OOD formulation provides sustained oxycodone plasma concentrations over the dosing interval of 24 hours and is suitable for once-daily administration. Bioavailability of OOD could be classified as comparable to the twice-daily administration of the OTD reference formulation. The new formulation widens and optimizes the range of strong opioid drug products in patient-centered therapy of chronic pain with simplified dosing and better compliance.

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Section: Discussionsupporting

confidence: 75%

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet

Scheidel¹,

Maritz²,

Gschwind³

et al. 2017

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“…(Kokki et al 2004), intranasally (i.n.) (Takala et al 1997;Dale et al 2002), subcutaneously (s.c.) (Kokubun et al 2014), bucally (Kokki et al 2004), rectally (Tegon et al 2009;Li et al 2011), epidurally (Kokki et al 2014), and orally (Mandema et al 1996;Bass et al 2012;Mundin et al 2012;Kim et al 2015) using immediate release (IR) solutions and immediate-and controlled-release tablets to diverse disease populations for the treatment of acute, and chronic nonmalignant pain and cancer pain (Hanks et al 2001;Radbruch and Nauck 2002;Lux et al 2014;Mehta et al 2014;Stessel et al 2014;Poelaert et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

Li¹,

Sun

Palmisano³

et al. 2016

Pharmacology Res & Perspec

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Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate‐release or controlled‐release formulations, under different administration routes, and in diverse populations. Longer terminal half‐lives from extravascular administration as compared to IV administration have been attributed to flip‐flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip‐flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time‐varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half‐lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate‐dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip‐flop and offered new insight for the development of modified release formulations and clinical use of oxycodone.

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“…The reported mean/median ages of the participant populations in the studies ranged from 45 years to 68.8 years. Eleven of the studies were crossover trials (published in 16 articles),12 16–30 and 12 were parallel-group trials (published in 13 articles),13 31–42 with 8 of the studies conducted in the USA,16 17 20 21 29 30 33 35 36 39 2 in Canada,18 22 3 in Finland,23–25 3 in China,13 40 42 3 in Italy31 34 41 and one each in Germany/Poland/Switzerland,12 Australia,28 Brazil,27 the UK37 38 and Japan/Korea 32. The length of the trials ranged from single-dose treatment to 1 year, and the studies reported the following comparisons:

CR oxycodone versus IR oxycodone29 30 33 36 39

CR oxycodone versus extended-release (ER) oxycodone12

CR oxycodone versus CR morphine,18 19 23 24 27 31 34 35 37 38 41 42 with one of these studies including a further two arms of transdermal (TD) buprenorphine and TD fentayl,31 and one of the studies comparing two different brands of slow-release morphine to CR oxycodone42

CR oxycodone versus CR hydromorphone22

CR oxycodone versus ER hydromorphone13

CR oxycodone versus ER oxymorphone20 21

CR oxycodone versus ER tapentadol32

CR oxycodone versus TD fentanyl31 40

CR oxycodone versus TD buprenorphine31

intravenous oxycodone versus rectal oxycodone28

intravenous oxycodone followed by IR oxycodone versus intravenous morphine followed by IR morphine25 26

intramuscular (IM) oxycodone vs oral oxycodone16

IM oxycodone versus IM morphine versus IM codeine 17

…”

Section: Resultsmentioning

confidence: 99%

“…We limited imputation of missing data to the imputation of missing SDs, either by calculating the SD if enough information was available or by using SDs from similar samples or studies, both according to the methods outlined by Higgins and Green 11. We only imputed SDs for pain intensity for Lux et al ,12 which were not reported for the subgroup of participants with malignant pain, by using the reported SDs for the whole sample of participants with either malignant (n=31) or non-malignant pain (n=15), and for Yu et al 13 for the primary outcome of the study ‘mean pain at its worst in the past 24 hours’ by using the SDs for the same outcome measured at baseline in the full analysis set. It was not possible to assess the impact of missing data in sensitivity analyses due to the low number of included studies within each comparison.…”

Section: Methodsmentioning

confidence: 99%

Efficacy, tolerability and acceptability of oxycodone for cancer-related pain in adults: an updated Cochrane systematic review

Schmidt‐Hansen

Bennett

Arnold

et al. 2018

BMJ Support Palliat Care

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Oxycodone offers similar levels of pain relief and adverse events to other strong opioids. However, hallucinations occurred less with CR oxycodone than with CR morphine, but the quality of this evidence was very low, so this finding should be treated with utmost caution. Our conclusions are consistent with other reviews and suggest that oxycodone can be used first line as an alternative to morphine. However, because it is cheaper, morphine generally remains the first-line opioid of choice.

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Cited by 9 publications

References 33 publications

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

Efficacy, tolerability and acceptability of oxycodone for cancer-related pain in adults: an updated Cochrane systematic review

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