TS2022 - Focus Group 3

Focus Group 3 - Best practices for conversion of immediate release approved ARVs: To prodrug or not to prodrug?

What Drugs or Drug Classes are Amenable to Prodrug Derivitization?

Creating LA prodrug formulations depends on water-insoluble drugs, yet many current drugs are water-soluble (e.g., nucleoside analogs).

  • Nucleoside analogs are the backbone of HIV care – need to explore how to prodrug this class of drugs to improve the quality of care given their drug resistance profile.
  • Creating a combination product is difficult – UNMC began with HIV prevention.

Five topics in prodrug development.

  • Optimize drug hydrophobicity: nucleosides are challenging – INSTIs are easiest (CAB, BIC and DTG prodrugs created with t1/2 of one year); PIs are most difficult.
  • Fine-tune drug hydrophobicity and pair with excipients and surfactants to be water-soluble.
  • Optimize the prodrug moiety structure and stability change linker and linker position, length of the carbon chain, and the use of active agent dimers and trimers.
  • Optimize chemical and enzymatic hydrolysis rates of the prodrug to the active agent.
  • Aim to create stable nanocrystals in depot cells and predominantly mononuclear phagocytes at the injection site or lymphatic system.

Prodrug development considerations.

  • Various reasons for using prodrugs: Improve bioavailability; target specific cell or tissue uptake and improve uptake; improve compatibility with dosage formulation; and extend duration of effectiveness via non-oral dosing.
  • Critical to understand the duration of drug presence and effectiveness, safety, and methods for depot removal.
  • Goals must drive research: Are we trying to improve absorption, clearance, safety, liver metabolism, targeting the drugs to a specific site, duration of effectiveness, etc.?

Why aren’t protease inhibitors a LA target?

  • Half-life is relatively short and may still require ritonavir, even if dosed non-orally.
  • Potency requires a large dose.
  • Local inflammation observed in various models.
  • Active agent is associated with a substantial number of complex DDIs – raises concerns about long-term management as a LA product.
  • The field appears to be moving away from PIs, so interest is waning.

Merits of Systemic Prodrug Delivery vs Prodrugs that Fully Hydrolyze Before Absorption

A goal for a prodrug should be to improve the therapeutic distribution to the site of action and reduce adverse events.

  • Concerns about LA drug clearance and mechanisms for eliminating the drug quickly in cases of toxicity or appearance of drug resistance.
    -- OLI is not practical given the clinical characteristics of patients that would benefit from LA regimens.
  • All derivatives of the product need to be followed.
  • Optimization of size and shape and selection of surfactants may be the most critical components in developing prodrugs that are effective and safe.
    -- Drug-linker-tail model – excipients and size and shape of the 100nm and 200nm nanocrystal impact how crystal and drug dissociate and hydrolyze from the depot.

Importance of the prodrug tail in HIV, TB and HCV and how we think about LA duration and effectiveness.

Challenge of targeting to the lung (TB) or liver (hepatitis) while developing a drug with a duration appropriate to the need.
Importance of the tail depends on the duration of treatment – HCV cure (8 weeks) vs drug-susceptible TB (4-6 mo) vs HIV (lifelong).
Need to be diligent about monitoring drugs during the tail to ensure no unintended consequences, such as sub-therapeutic doses that could lead to drug resistance.

Impact on Non-Clinical Safety Package?

FDA advice and preclinical work depends on the parent product and is case-specific

  • Variables include: what is known about safety, how much of that data can be leveraged, what are you doing to that product, and how it will be delivered.
  • The lifetime of the product in circulation matters.
    -- Suitable nonclinical safety and PK exposure models must be identified to measure the prodrug, metabolites, and the active agent.
    -- If the product breaks down quickly, and the prodrug is mostly undetectable or undetectable, then could potentially leverage existing oral data.
    -- The nature of the metabolites is critical. If the prodrug is radically different from the API, you will need to do more. If the PK and the metabolite are not that different from the original product, an abridged preclinical program might be possible.
    -- Anticipate performing some bridging studies.
  • Novel excipients and involvement of a device will change the course of action. If the product is combined with a device, biocompatibility of those materials must be studied. ISRs and safety of excipients will need to be studied.

Given that PK is a surrogate, could it be misleading to use oral PK to guide a non-oral program?

  • ADME of oral vs non-oral delivery – absorption could be dominant for oral drugs, and clearance could be dominant for non-oral formulations.
  • Focused on the safety aspect – you would assess organ distribution and organ toxicity. It would be a good sign if non-oral PK safety and toxicity profiles are comparable to the oral drug profiles.

Does the nonclinical safety package depend on targeting treatment versus prevention?

  • FDA would not be that flexible for a prevention product given that the target audience is people at high risk but otherwise healthy. There is a different risk-benefit ratio for treatment versus prevention.
  • Even if a product is specifically targeted for prevention, treatment studies may still be required – you may need to include a small preclinical treatment package.

Children vs Adults?

Began with the assertion that typically, we try to extrapolate from adult studies.

  • Children require a smaller doses – the ideal scenario would be a two-month drug dose at birth, followed by six-month incremental dosing.
  • Need to address variability and absorption, metabolism differences, and metabolism changes as the child ages.
  • Need to address differences in absorption and distribution of a drug or prodrug and the impact of the nanomaterial following IM or SQ administration in a baby.

Examples of changes in prodrug conversion rates as a function of age or weight of a baby.

  • Various esterases mature with the baby, but unsure if this translates into any clinically relevant changes in PK.
  • Transport systems mature in babies and could affect PK.
  • Gut pH in babies (4.5) is higher than an adult and can affect the release of an encapsulated drug. Taste-masking LPV – no drug was released when administered in the first 2 weeks of life.
  • Carboxylesterases increase by 2-3 fold from <3 weeks to ≥6 years old (https://pubmed.ncbi.nlm.nih.gov/26825642/).

Using in-vivo and in-silico models to help with infant studies.

  • FDA will look at safety in NHP models, but does not use PK data as a surrogate for infants – the developmental profiles of NHPs and human infants are different.
  • In-silico models must account for size, volume and function and include a continuous growth mode – be mindful about children’s growth and maturation; Model validation is important.