BE of liposomal parenterals: suggestions based on discussions at GBHI-3 Conference, Amsterdam/2018 Henning H. Blume, PhD DSc SocraTec C&S, Oberursel/Germany Concepts and Strategies in Clinical Drug Development www.socratec.eu 3rd symposium on bioequivalence requirements Amman/Jordan, May 2/3, 2018

Issues discussed at GBHI-3 Analyte(s) to be measured (example: doxorubicin) current regulatory thinking … similar/identical requirements defined by EMA and US-FDA minimum: encapsulated and non-encapsulated doxorubicin … challenged during the conference scientific rationale for such comprehensive requirement? risk to fail BE for non-encapsulated DXR, if encapsulated is BE? BSA-related dosing: adjustment in case of BW change? significant impact of BSA/BMI/BW on systemic exposure? what should/needs to be done in case of BW change? can limits be defined for a "non-relevant" BW change?

Caelyx®: encapsulated vs. "free" DXR taken from Dr. Langguth's presentation curves decline in parallel

Systemic exposure/PK Myocet® Plasma profiles after i.v. Myocet® Mross et al., 2004 … reflecting "free" DXR curves decline in parallel

Release from liposomes controls PK Plasma profiles of two different types of liposomes Gabizon et al., 1989 PEGylated liposomes (example: Caelyx®) non-PEGylated liposomes (example: Myocet®) "free" DXR non-encapsulated  total DXR  encapsulated DXR  free DXR profiles characterized by release from liposomes DXR half-life non-encapsulated: 10 min; >50 h (ß-phase) encapsulated: ~ 55 h total DXR of Myocet® elimination determined by release from leucocytes

Release from liposomes controls PK Plasma profiles of two different types of liposomes Gabizon et al., 1989 PEGylated liposomes (example: Caelyx®) non-PEGylated liposomes (example: Myocet®) "free" DXR non-encapsulated  total DXR  encapsulated DXR  free DXR curves decline in parallel

Conclusions on appropriate analyte Convincing evidence release from liposomes is controlling/determining process other PK processes follow "flip-flop" conditions final elimination of DXR occurs from "deep compartment" Conclusion BE demonstrated for encapsulated DXR … … should "guarantee" BE for "free" (non-encapsulated) DXR final evidence should be derived from failed studies … … normally not published (should be available to the Authorities…) Consequence regulatory requirements to be revised (only encapsulated) … … EMA seems to consider this, FDA still more reluctant

Adjustment to body weight changes? another case of Fake News …???

Adjustment to body weight changes? Problem statement BW can rapidly change in patients (e.g. water in tissues) … … and dose may need to be adjusted accordingly consequence: different doses for within-subject comparison What might be appropriate handling? option: "dose normalisation" between periods significant obstacle: Authorities don't like it (so far) alternative: BE assessment with different doses makes BE conclusion less likely & scientifically not sound Question for the clinical pharmacist (Prof. Hempel) PK/exposure affected by change in BW and consequences ? which solution(s) may be adequate/recommendable?

BW change or change in BSA?

Impact of BW/BSA change on AUC

Impact of BW/BSA change on Cmax

Conclusions on dose adjustment Impact of BW/BSA changes on exposure changes in BSA and body weight differ … 10% ( 15%) change in BW  4.3% (6.4%) change in BSA … BSA is clearly more predictive than body weight 10% ( 15%) change in BW  4.2% (6.4%) in AUC and Cmax Conclusions BW changes exceeding certain level need to be considered BSA better predictor for anticipation of changes in exposure Consequences, suggestions dose adjustment according to BSA change … … should keep dosages proportional (proper basis for BE) FDA:

BE of liposomal parenterals: suggestions based on discussions at GBHI-3 Conference, Amsterdam/2018 Henning H. Blume, PhD DSc SocraTec C&S, Oberursel/Germany Concepts and Strategies in Clinical Drug Development www.socratec.eu 3rd symposium on bioequivalence requirements Amman/Jordan, May 2/3, 2018