1. 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
3rd symposium on bioequivalence requirements
Amman/Jordan, May 2/3, 2018

2. 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?

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

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

5. 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

6. 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

7. 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

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

10. 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?

11. BW change or change in BSA?

12. Impact of BW/BSA change on AUC

13. Impact of BW/BSA change on Cmax

14. 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:

15. 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
3rd symposium on bioequivalence requirements
Amman/Jordan, May 2/3, 2018