Long acting (LA) drug delivery in TB treatment

Andrew Owen, Ph.D. FRSB. FBPhS.Professor of Pharmacology

Department of Molecular and Clinical PharmacologyUniversity of Liverpool, UK

How to define “long-acting”?The term is traditionally applied in a disease- and/or drug-specific manner (e.g. Insulin glargine is termed LA for once daily administration and the term ‘ultra-LA’ for insulin Degludec is now being introduced).

Route of delivery Oral Parenteral Implant / Device

Dosing frequency ≥ 1 week ≥ 1month ≥ 6monthsOwen and Rannard. ADDR. 2016

Technologies being explored across indications to achieve long-acting delivery

Injectables Devices

Owen and Rannard. ADDR. 2016

• Directly Observed Therapy (DOT) was estimated to account for up to 75% of healthcare provider costs for TB treatment1

• The current WHO End TB Strategy2 contains “supportive treatment supervision by treatment partners”. Many TB programs still use DOT.

• DOT not shown to be significantly superior to self-administered treatment2

Non-adherence as a driver for development of long-acting medicines

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1Steffen R, Menzies D, Oxlade O, et al. Patients’ costs and cost-effectiveness of tuberculosis treatment in and non-DOTS facilities in Rio de Janeiro, Brazil. PLoS One. 2010;5:1–7.2World Health Organization. The End TB Strategy. Global strategy and targets for tuberculosis prevention, care and control after 2015. 2014. www.who.int/tb/post2015_strategy/en/.

High drug potency underpins the LA approach

Dose and release rate as critical factors in LA delivery

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K = 0.0046 hr-1

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Particles in liquid

Nanotechnologies being explored in drug deliverySolid Drug Nanoparticles (SDNs; aka nanocrystals, nanosuspensions, nanodispersio

“Bottom-Up”

Precipitation of solutions

“Top-Down”

Breaking largesolids

Nanocarrier systems (extremely diverse in composition)

Lipid-based carriers polymer-based carriers Inorganic carriers Biological

Grinding Pharmaceuticals• Physical fracturing of “large” fragments to generate small particles

– Micronisation (Dry or air-jet milling - sizes 1-5µm)– Wet bead (or nano) Milling - <1µm

• Attrition techniques– Limited to materials with specific

properties (eg Crystalline, high melting point)

– Limited access to approved excipients– Impurities from milling agents– Correlation between processing time

or energy input and particle size• BUT successful in new medicine

development

Liverpool ETFD formation of nanosuspensions(Being employed as part of R01AI114405)

Two solventsAPIs and excipients dissolved

In vitro In Silico In Vivo

McDonald et al. Adv Healthc Mater. 2013 Sep 1. doi: 10.1002/adhm.201300280.

Existing long acting depot agents

Paliperidone palmitate

Respiridone

Medroxyprogesterone acetateOlanzapine pamoate

Rilpivirine Cabotegravir

Key physiochemical and pharmacokinetic characteristics of LAIs

Isoniazid

Compatibility of existing TB agentsIsoniazid Rifampicin

Pyrazinamide Ethambutol

Compatibility of newer TB agentsRifabutin Rifapentine

Delamanid Bedaquiline

Potential for overall reduction in dose

Caveats- Not always given for the same indication- Oral medicines not always prodrugs

What about pharmacogenetics variability?

How to define the target concentration for LA? Not 2h concentration, AUC?

Will genetics / body weight influence dose frequency?

??

Avoidance of the intestinal barrier to absorption would be expected to reduce inter-patient variability

However, LA formulations appear to be as variable in terms of PK as their oral counterparts:

What are the mechanisms for drug absorption following depot administration??

Drug Oral PK variability (AUC CV%) LA PK variability (AUC CV%)

Paliperidone 35.3 40%

Olanzapine 26% 50%

Medroxyprogesterone 52% 34%

Rilpivirine 39% 52%*

Cabotegravir 27% 39%

Owen and Rannard. ADDR. 2016

SDNs for long-acting depot delivery of HIV drugs: mechanisms?

Lymph capillary Interstitial spaceMuscle cells

?

?

Many unanswered questions regarding what regulates drug release!

Owen and Rannard. ADDR. 2016Darville, et al. J Pharm Sci, 103 (2014) 2072-2087.

What about drug-drug Interactions with LAI?

van de Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov. 2003 Mar;2(3):192-204. Review.

- Potential for lower hepatic and intestinal concentrations?

- Impact on enzyme / transporter induction

Some key considerations for long-acting therapies (not mutually exclusive and probably not comprehensive)• Process-specific considerations

– Cost– Scalability– Sterility– Compatibility with preferred APIs

• Drug-specific considerations– Loading (volume of depot)– Combinations– Adverse drug reactions– Drug-drug interactions

• Release characteristics– Achievable plasma (target) concentrations– Duration of exposure (plasma versus target)– Consistency / reproducibility– Tuneability?

• Compatibility with healthcare systems (training?)• Patient acceptability

Drug(s) Formulation

Device

TPP

Opportunities and challengesDose reduction (and associated cost)?

Avoidance of gastrointestinal AE’s

Improved patient “adherence”

Compatibility with DOT

Better protection of health privacy

Inter-patient variability (inc time)?

Large injection volume / ISR?

Drug-drug interaction potential?

Requirement for oral lead-in?

Consequences of missed doses for resistance?

Developed with R24AI118397

Acknowledgements

www.BritishSocietyNanomedicine.org

The Liverpool Team

CHAIPaul DomanicoMelynda Watkins

SSATMarta BoffitoAkil JacksonEmilie Elliot

Marco Siccardi Neill LiptrottSteve RannardDavid Back Tom McDonaldSaye KhooGerry Davies

Chris DavidPierre ChambonFiona HattonSam AutyAndy DwyerHannah RogersFaye HernJane FordHelen CauldbeckMaude LeHellayeRebecca SlaterTamara AlhilfiMarco GiardielloSteph EdwardsMartin LevereAdam Town

Sharon MurphyDeirdre EganLaura DickinsonLaura Else Sara GibbonsHelen Reynolds Paul CurleyAlessandro Schipani Darren Moss Lee TathamJames HobsonRajith Kumar ReddyMegan NearyChristina ChanJustin ChiongHenry Pertinez Rana AbutaimaRohan GurjarSharon MurphyAna Jimenez-ValverdeHannah KinvigNuala KeeganLouise Tidbury

MPPYao ChengSandeep Juneja