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AOAC INTERNATIONAL STAKEHOLDER PANEL on DIETARY SUPPLEMENTS Katerina Mastovska, Covance Laboratories PDE5 Inhibitors Working Group Chair September 5, 2014

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AOAC INTERNATIONAL STAKEHOLDER PANEL on DIETARY SUPPLEMENTS Katerina Mastovska, Covance Laboratories PDE5 Inhibitors Working Group Chair September 5, 2014 AOAC INTERNATIONAL STAKEHOLDER PANEL ON DIETARY SUPPLEMENTS Katerina Mastovska, Covance Laboratories PDE5 Inhibitors Working Group Chair September 5, 2014 Boca Raton Resort, Boca Raton, Florida Technical Background • What are PDE5 inhibitors? • Why are they an issue in dietary supplements? • What are the analytical challenges? Phosphodiesterase Type 5 (PDE5) Inhibitors • Used in the treatment of erectile dysfunction (ED) and also explored for the treatment of pulmonary hypertension • Block degradative action of PDE5 on cyclic guanosine monophosphate (cGMP) in smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis (and arterial walls within the lungs) cGMP • cGMP = second messenger relaxing smooth muscle tissues, leading to the increased blood flow in blood vessels PDE5 Inhibitors – Mechanism of Action cGMP Approved PDE5 Inhibitor Drugs In the US: • Sildenafil (Viagra®, Pfizer, 1998) • TdlfilTadalafil (Cialis®, Elli Lilly, 2003) • Vardenafil (Levitra®, Bayer, 2003) • Avanafil (Stendra®, Vivus, 2012) Other countries: • Udenafil (Zydena®, Dong‐A Pharmaceutical Co. Ltd) in South Korea and Malaysia • Mirodenafil (Mvix®, SK Chemicals Life Science) in South Korea • Lodenafil carbonate (Helleva®, Cristália Produtos Quími‐cos e Farmacêuticos) in Brazil Approved PDE5 Inhibitor Drugs Patel et al. , J. Pharm. Biomed. Anal. 87 (2014) 176– 190 Adverse PDE5 Inhibitor Drug Side‐Effects • Nausea • Nasal congestion • Headache • Palpitation • Abdominal pain • Tachycardia • Back pain • Rash • Photosensitivity • Itch • Abnormal vision • Priapism • Eye pain • Heart attack • Sudden hearing loss • Life‐threatening drug • Hypotension interactions (e.g. with • Face edema nitrates and cardiac • Joint and muscle pain antiarrhythmic drugs) Adulteration of Dietary Supplements with Synthetic PDE5 Inhibitors Adulteration of Dietary Supplements with Synthetic PDE5 Inhibitors • Serious problem – Potential serious adverse (even lethal) health affects – Adulteration with approved drugs but also their unapproved analogs (unknown toxicological effects) – High incidence of adulteration Campbell et al., J. Sex. Med. 10 (2013) 1842‐1849: ‐ 81% out of 91 tested herbal products adulterated with synthetic PDE5 inhibitors and their analogs Adulteration of Dietary Supplements with Synthetic PDE5 Inhibitors 77% of the products contained synthetic drugs and their analogs FDA‐CDER Tainted Supplement Database 505 entries, 2007 – 2014, retrieved 3/7/2014 FDA‐CDER Tainted Supplement Database Sildenafil & analogs Tadalafil & analogs 1% Vardfildenafil & analogs 23% 76% 2007 – 2014, retrieved 3/7/2014 Analytical Challenges • Number of potential synthetic PDE5 inhibitors: – more than 100 known analogs – more than 50 analogs reported as adulterants • Availability of reference standards • Inventiveness of adulterators: – exotic analogs – mixtures of analogs – embedding of adulterants into capsule walls • Complex and variable dietary supplement matrices Fitness for Purpose (1) Screening Method (2) Identification/Determination Method Fitness for Purpose “Scr eenin g Method ” The method must be able to screen known and unknown (unexpected) PDE5 inhibitors in various dietary supplement matrices. Fitness for Purpose “Identification/Determination Method” The method must be able to identify known and unknown (unexpected) PDE5 inhibitors in various dietary supplement matrices. Ideally, the method should combine targeted and non‐targeted approaches, with the ability to quantitate PDE5 inhibitors for which reference standards are available. PDE5 Inhibitors Working Group: Members . Katerina Mastovska, Covance (Chair) . Joe Betz, NIH . Anton Bzhelyansky, USP . Anatoly Chlenov, PerkinElmer . Teresa Cain, FDA . John Edwards, Process NMR . Jana Hildreth, Blaze Science Industries . Todd Koch, Pfizer . David Kennedy, Phenomenex . Alexander Krynitsky, FDA . James Neal‐Kababick, Flora Research . Stephen Lock, AB SCIEX . Melissa Phillips, NIST . Elisa Nickum, FDA . Steve Royy,ce, Agilent . Catherine Rimmer, NIST . John Travis, NSF International . Brian Schaneberg, Starbucks . Lukas Vaclavik, FDA . Olga Shimelis, Supelco . Jerry Zweigenbaum, Agilent . Garrett Zielinski, Covance PDE5 Inhibitors Working Group: Work to Date • 8 teleconferences (May 2014 –July 2014) • 3 SMPRs DftdDrafted • Screening Method for PDE5 Inhibitors • Identification of PDE5 Inhibitors • Determination of PDE5 Inhibitors • 30 day public comment period (July 25, 2014 – August 25, 2014) • SMPRs made ready for SPDS review and approval SMPRs Key Points: Target Compound Panel • Acetaminotadalafil • Acetildenafil • Avanafil • Homosildenafil • Hydroxyacetildenafil • Hydroxyhomosildenafil • Hydroxythiohomosildenafil • Lodenafil carbonate • Mirodenafil • Proppypyoxyphenylhyyydroxyhomosildenafil • Sildenafil • Tadalafil • Thiohomosildenafil • Udenafil • Vardenafil SMPRs Key Points: Matrices • Tablets • Capsules (both the content and the capsule shells) • Softgels • Gelcaps • Liquids • Powders • Extracts SMPR Key Points: Screening Method • Intended Use: Routine surveillance of dietary ingredients and products by a trained technician. • Applicability: Qualitative assay for PDE5 inhibitors in dietary ingredients and supplements. • Maximum Time‐To‐Result: 1 hour • Non‐Target Compound Panel: Shall be developed for the selectivity study based on the used analytical technique. SMPR Key Points: Screening Method Minimum Target Test Parameter Parameter Requirements Acceptable Concentration Results Minimum of 33 replicates POD @ low per matrix type, spiked at 100 ppm 90% POD§ concentration or below the designated low level target test conc. Validation Minimum of 5 replicates ratory POD @ high per matrix type spiked at o 10 x low conc. 100% correct concentration 10x the designated low Lab analyses are level target test conc. expected per Single matrix type POD @ zero Minimum of 5 replicates 0 ppm concentration per matrix type. § 95% confidence interval SMPR Key Points: Screening Method Minimum Parameter Target Test Parameter Acceptable Requirements Concentration Results low ≥ 0.85§ Use Appendix N: concentration ISPAM Guidelines for Validation LPOD Validation of Qualitative Binary 10 x low conc. ≥ 0.95§ Chemistry Methods. aboratory L ‐ § LPOD (0) 0 ppm ≤ 0.05 Multi § 95% confidence interval SMPR Key Points: Screening Method Selectivity Study: Minimum Final Parameter Parameter Requirements Acceptable Test Conc. RltResults Test each target compound listed in Low 100% Target Annex II at the final test concentrat positive concentration. ion results** Test each non‐target panel Validation compound at the final test concentration or at the highest ratory o expected matrix concentration in ≥95% 10 x low Non‐target the case of naturally occurring negative Lab conc. matrix components. A list of results potential non‐target compounds Single for immunoassays is provided in Annex III. **100% correct analyses are expected. Some aberrations may be acceptable if the aberrations are investigated, and acceptable explanations can be determined and communicated to method users. SMPR Key Points: Identification Method • Intended Use: Reference method for dispute resolution. • Applicability: Identification of PDE5 inhibitors in dietary ingredients and supplements. • Identification Method: A method that is capable of identifying the PDE5 inhibitors listed in Annex II and providing at least class identification of other PDE5 inhibitors based on their structural similarity to the compounds lis te d in Annex II . The iden tifica tion shldhould be done using technique‐specific, generally acceptable criteria, such as those given in 2002/657/EC. • Maximum Time‐To‐Result: No maximum time. SMPR Key Points: Identification Method Minimum Target Test Parameter Parameter Requirements Acceptable Concentration Results Minimum of 33 replicates 90% POI§ of representing all target the pooled POI @ low compounds in Annex II and all 100 ppm data for all concentration matrix types listed in Annex III, target spiked at or below the designated compounds low level target test conc. and matrices Validation Minimum of 5 replicates per POI @ high matrix type spiked at 10x the boratory 10 x low conc. La concentration designated low level target test 100% correct conc. analyses are Single expected POI @ zero Minimum of 5 replicates per 0 ppm concentration matrix type. § 95% confidence interval SMPR Key Points: Screening Method Minimum Parameter Target Test Parameter Acceptable Requirements Concentration Results low ≥ 0.85§ Use Appendix N: concentration ISPAM Guidelines for Validation LPOI Validation of Qualitative Binary 10 x low conc. ≥ 0.95§ Chemistry Methods. aboratory L ‐ § LPOI (0) 0 ppm ≤ 0.05 Multi § 95% confidence interval SMPR Key Points: Determination Method • Intended Use: Reference method for dispute resolution. • Applicability: Quantitative method for PDE5 inhibitors in dietary ingredients and supplements for use in testing laboratories by trained technicians. • Maximum Time‐To‐Result: No maximum time. SMPR Key Points: Determination Method Analytical range 50 ‐ 200 ppm y r Limit of Quantitation (LOQ) ≤ 50 ppm Repeatability (RSD ) ≤ 20% Laborato r Validation 70% to 120% of mean Single Recovery spiked recovery over the analytical range Lab ‐ Reproducibility (RSDR) ≤ 30% Multi Validation Motion • Move to accept the Standard Method Performance Requirements for Screening Method for PDE5 Inhibitors as presented. Discussion? Motion • Move to accept the Standard Method Performance Requirements for Identification of PDE5 Inhibitors as presented. Discussion? Motion • Move to accept the Standard Method Performance Requirements for Determination of PDE5 Inhibitors as presented. Discussion?.
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