Dosing Patterns during Conversion to IPX066, Extended-Release Carbidopa-Levodopa (ER CD-LD), in Parkinson's Disease with Motor Fluctuations

John C Morgan, Rohit Dhall, Robert Rubens, Sarita Khanna, Suneel Gupta, John C Morgan, Rohit Dhall, Robert Rubens, Sarita Khanna, Suneel Gupta

Abstract

Background: IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours.

Objective: To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations.

Methods: Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The "converted" daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry.

Results: The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses ≥800 mg and dose frequencies ≥6 tended to have higher rates of discontinuation during conversion to ER CD-LD.

Conclusions: Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (≤1250 mg) and dose frequencies (<7) of LD, final mean dose ratios were within tight ranges of 2.1 to 2.4 for IR CD-LD (ADVANCE-PD) and 2.4 to 2.8 for CLE (ASCEND-PD) and were generally independent of the LD dosing frequency at study entry. These trials are registered with NCT00974974, NCT01130493.

Figures

Figure 1
Figure 1
Final daily LD dose ratios (black bars) and ER CD-LD daily dosing frequency (gray bars) based on daily LD dose ranges at study entry for the conversion from IR CD-LD (a) or CLE (b).
Figure 2
Figure 2
Final daily LD dose ratios (black bars) and ER CD-LD daily dosing frequency (gray bars) based on daily LD dosing frequency at study entry for the conversion from IR CD-LD (a) or CLE (b).
Figure 3
Figure 3
Proportions of participants who discontinued during dose conversion based on daily LD dose ranges at study entry during the conversion from IR CD-LD (a) or CLE (b). Proportions were calculated using the total number of participants who entered dose conversion (n=450 in (a) n=110 in (b)). The numbers of participants who discontinued from each dose range are indicated within each bar. The dashed lines represent the overall rate of discontinuation during dose conversion in each study.
Figure 4
Figure 4
Proportions of participants who discontinued during dose conversion based on daily LD dose frequency at study entry during the conversion from IR CD-LD (a) or CLE (b). Proportions were calculated using the total number of participants who entered dose conversion (n=450 in (a) n=110 in (b)). The numbers of participants who discontinued from each dose range are indicated within each bar. The dashed lines represent the overall rate of discontinuation during dose conversion in each study.

References

    1. LeWitt P. A., Fahn S. Levodopa therapy for Parkinson disease: a look backward and forward. Neurology. 2016;86(14):S3–S12. doi: 10.1212/wnl.0000000000002509.
    1. LeWitt P. A. Levodopa for the treatment of Parkinson’s disease. New England Journal of Medicine. 2008;359(23):2468–2476. doi: 10.1056/nejmct0800326.
    1. Olanow C. W., Obeso J. A., Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurology. 2006;5(8):677–687. doi: 10.1016/s1474-4422(06)70521-x.
    1. Cedarbaum J. M. Clinical pharmacokinetics of anti-parkinsonian drugs. Clinical Pharmacokinetics. 1987;13(3):141–178. doi: 10.2165/00003088-198713030-00002.
    1. Nutt J. G., Woodward W. R., Anderson J. L. The effect of carbidopa on the pharmacokinetics of intravenously administered levodopa: the mechanism of action in the treatment of parkinsonism. Annals of Neurology. 1985;18(5):537–543. doi: 10.1002/ana.410180505.
    1. Obeso J. A., Rodriguez-Oroz M. C., Chana P., Lera G., Rodriguez M., Olanow C. W. The evolution and origin of motor complications in Parkinson’s disease. Neurology. 2000;55(11):S13–S20.
    1. Stacy M. Medical management of Parkinson’s disease. Neurologic Clinics. 2009;27(3):605–631. doi: 10.1016/j.ncl.2009.04.009.
    1. Cedarbaum J. M., Hoey M., McDowell F. H. A double-blind crossover comparison of Sinemet CR4 and standard Sinemet 25/100 in patients with Parkinson’s disease and fluctuating motor performance. Journal of Neurology, Neurosurgery and Psychiatry. 1989;52(2):207–212. doi: 10.1136/jnnp.52.2.207.
    1. Sage J. I., Mark M. H. Comparison of controlled-release Sinemet (CR4) and standard Sinemet (25 mg/100 mg) in advanced Parkinson’s disease: a double-blind, crossover study. Clinical Neuropharmacology. 1988;11(2):174–179. doi: 10.1097/00002826-198804000-00009.
    1. Deleu D., Jacques M., Michotte Y., Ebinger G. Controlled-release carbidopa/levodopa (CR) in parkinsonian patients with response fluctuations on standard levodopa treatment: clinical and pharmacokinetic observations. Neurology. 1989;39(11):88–92.
    1. Hauser R. A., Ellenbogen A. L., Metman L. V., et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease. Movement Disorders. 2011;26(12):2246–2252. doi: 10.1002/mds.23861.
    1. Hauser R. A., Hsu A., Kell S., et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurology. 2013;12(4):346–356. doi: 10.1016/s1474-4422(13)70025-5.
    1. Stocchi F., Hsu A., Khanna S., et al. Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients. Parkinsonism and Related Disorders. 2014;20(12):1335–1340. doi: 10.1016/j.parkreldis.2014.08.004.
    1. Nausieda P. A., Hsu A., Elmer L., et al. Conversion to IPX066 from standard levodopa formulations in advanced Parkinson’s disease: experience in clinical trials. Journal of Parkinson’s Disease. 2015;5(4):837–845. doi: 10.3233/jpd-150622.
    1. LeWitt P. A., Metman L. V., Rubens R., Khanna S., Kell S., Gupta S. Effect of concomitant medications on the safety and efficacy of extended-release carbidopa levodopa (IPX066) in patients with advanced Parkinson’s disease: a post hoc analysis. Clinical Neuropharmacology. 2018;41(2) doi: 10.1097/WNF.0000000000000269.
    1. Hsu A., Yao H. M., Gupta S., Modi N. B. Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066), with immediate-release carbidopa-levodopa (Sinemet®), sustained-release carbidopa-levodopa (Sinemet® CR), and carbidopa-levodopa-entacapone (Stalevo®) Journal of Clinical Pharmacology. 2015;55(9):995–1003. doi: 10.1002/jcph.514.
    1. Hughes A. J., Daniel S. E., Kilford L., Lees A. J. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery and Psychiatry. 1992;55(3):181–184. doi: 10.1136/jnnp.55.3.181.
    1. Hoehn M. M., Yahr M. D. Parkinsonism: onset, progression and mortality. Neurology. 1967;17(5):427–442. doi: 10.1212/wnl.17.5.427.
    1. Kianirad Y., Simuni T., Zadikoff C., Bega D., Afshari M., Jonnalagadda S. Experience with utilitzation of rytary in the clinical setting. Proceedings of 20th International Congress of Parkinson’s Disease and Movement Disorders; June 2016; Berlin, Germany. p. p. S644.
    1. LoRusso S. J., Ouyang B., Barton B. R. Conversion of patients from immediate-release carbidopa-levodopa (IR CD-LD) and sustained-release carbidopa-levodopa (CR CD-LD) to extended-release carbidopa-levodopa (ER CD-LD) in clinical practice. Proceedings of 20th International Congress of Parkinson’s Disease and Movement Disorders; June 2016; Berlin, Germany. p. p. S670.
    1. Espay A. J., Pagan F. L., Walter B. L., et al. Optimizing extended-release carbidopa/levodopa in Parkinson’s disease. Neurology: Clinical Practice. 2017;7(1):86–93. doi: 10.1212/cpj.0000000000000316.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe