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[Amol1412845460]

Hello all,

I have a questions regarding calculation of volume of distribution and clearance for single dose of Amphotericin B injection. Study design is open label, randomized, two-treatment, two period, two-sequence, single dose, crossover, comparative pharmacokinetic study in healthy adult human subjects under fed conditions.

Study was carried out with following objective
To compare the rate and extent of absorption of amphotericin B after intravenous
administration of single dose of Amphotericin B liposome for injection (each vial
containing amphotericin 50 mg encapsulated in liposomes) with that of AmBisome® liposome for injection (each vial containing amphotericin 50 mg encapsulated in liposomes) in healthy adult human subjects in a randomized crossover study under fed conditions. The plasma pharmacokinetics of free and liposomal amphotericin were evaluated.

Dose mode of administration is single dose of Amphotericin B liposome for injection (3 mg/kg body weight). Dose was given to subjects with respective subject weight
i.e. suppose subject No.01, weight 73 and dose 3mg/kg then total dose= 73 kg * 3 mg/kg =219 mg.
I had calculated administration VD and CL based on the non-compartmental model using IV infusion dose type. Following information’s was provided in dosing sheet in winNonlin software.

sub-1, period-1, dose-219mg, time of dose-0,
Length of Infusion-2

sub-1, period-2, dose-219mg, time of dose-0,
Length of Infusion-2.01
Plasma Concentration data is as below
Sub Seq Per Form Time (hr) Conc (μg/mL)
1 B 1 T 0 0
1 B 1 T 0.5 0
1 B 1 T 1 2.19
1 B 1 T 1.33 4.86
1 B 1 T 1.67 6.21
1 B 1 T 2 8.24
1 B 1 T 2.33 7.6
1 B 1 T 2.67 6.77
1 B 1 T 3 6.49
1 B 1 T 3.5 6.85
1 B 1 T 4 7.99
1 B 1 T 5 7.22
1 B 1 T 6 8.2
1 B 1 T 8 7.7
1 B 1 T 10 8.98
1 B 1 T 12 8.08
1 B 1 T 16 6.58
1 B 1 T 24 3.56
1 B 1 T 36 Missing
1 B 1 T 48 1.31
1 B 1 T 72 0.61
1 B 1 T 96 0.35
1 B 1 T 120 0.25
1 B 1 T 144 0.23
1 B 1 T 168 Missing
1 B 2 R 0 0
1 B 2 R 0.5 0
1 B 2 R 1 1.58
1 B 2 R 1.33 2.81
1 B 2 R 1.67 4.24
1 B 2 R 2 5.66
1 B 2 R 2.33 5.69
1 B 2 R 2.67 6.11
1 B 2 R 3 5.24
1 B 2 R 3.5 5.85
1 B 2 R 4 5.89
1 B 2 R 5 7.38
1 B 2 R 6 6.31
1 B 2 R 8 5.67
1 B 2 R 10 4.62
1 B 2 R 12 4.89
1 B 2 R 16 4.45
1 B 2 R 24 2.56
1 B 2 R 36 2.11
1 B 2 R 48 0.78
1 B 2 R 72 0.57
1 B 2 R 96 0.39
1 B 2 R 120 0.27
1 B 2 R 144 0.25
1 B 2 R 168 0

PK parameter calculations VD and CL values obtained from winNonlin were not matching with reference article
WinNonlin results of VD and CL is as below

Sub VD (mL) CL (mL/hr)
1 29759.19 833.3955
1 82120.74 1029.759

sub-1, period-1, VD (mL)-29759.19, CL (mL/hr)-833.3955
sub-1, period-2, VD (mL)-82120.74, CL (mL/hr)-1029.759

Could anyone please guide me how to estimate VD and CL in mL/kg and mL/hr/kg in winNonlin software.

In the NCA-setup by selecting option Normalization and kg. I get Vd in mL/Kg and clearance in mL/h/kg but till value were not matches with SPC report.

when I selecting option Normalization and g, I get same value as that of Normalization and kg.

Reference: Prescribing information of AmBisome® (amphotericin liposome for injection from Astellas Pharma US, Inc. [cited 18 December, 2013]. www.accessdata.fda.gov/drugsatfda_docs/l...12/050740s021lbl.pdf

Thanks in advance
Regards
Amol

Edited by Simon Davis, 28 October 2014 - 05:51 AM.
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[Simon Davis]

Amol, please attach your PHXPROJ, people's time is limited and setting up a project for you is unnecessary work if we can simply highlight the changes in your existing settings.

Furthermore can you clarify if you have the same individuals as in the paper?

The table on page 4 of the paper you reference is mean data at 3 dose levels on day 1 and last day, but you've give what appear to be an individual's results? so the questions I put you on the BEBAC forum remain (forum.bebac.at/mix_entry.php?id=13257#p13282)

What is your objective? I only briefly skimmed the paper but it's clear that they had problems estimating a 'true' half-life and also that there was some considerable variability - so why do you expect an exact match for an individual?

Simon

Edited by Simon Davis, 28 October 2014 - 05:51 AM.
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