Bioequivalence and Bioavailability Forum • CL and Vd calculations in WinNonlin

kumarnaidu
★

Mumbai, India,
2014-07-11 09:29
(3937 d 11:55 ago)

Posting: # 13257
Views: 10,947

CL and Vd calculations in WinNonlin [Software]

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.
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

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. Is there any option available to find out VD and CL in mL/kg and mL/hr/kg.

Thanks in advance

Edit: Unlinked from this post, category changed. [Helmut]

—
Kumar Naidu

Helmut
★★★

Vienna, Austria,
2014-07-11 16:17
(3937 d 05:06 ago)

@ kumarnaidu
Posting: # 13260
Views: 9,449

Unit conversions, F ≤1?

Post reply

Hi Kumar,

I don’t have spare time to check the setup. One question first: Which version of WinNonlin?

❝ PK parameter calculations VD and CL values obtained from winNonlin were not matching with reference article

Can you give us these values?

Remarks:

I have no experiences with this liposomal product, but I guess you don’t assume F=1 (otherwise why did you perform such a study?). If this is the case, infusion is not the correct NCA-model – use an extravasal model instead. Then you’ll get Vd/F and CL/F, where 0<F≤1 is unknown.
WinNonlin is notoriously bad in unit conversions. I guess you measured concentrations in ug/mL, right? It is a good idea to state the dose in the same mass-unit than the concentration, e.g., instead of 219 mg better use 219,000 ug.
For dose-normalizations you have two options:
1. Give not the administered total dose for each subject but the dose per kg bodyweight. In the NCA-setup select Normalization and kg. Then you’ll get e.g. the clearance in mL/h/kg.
2. Keep the current setup and transform the results (divide by the subject’s body weight). I’m not sure whether the unit of the result is correctly transformed in all version of WinNonlin. If not, change it (transformation/properties) accordingly.

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kumarnaidu
★

Mumbai, India,
2014-07-14 14:23
(3934 d 07:00 ago)

@ Helmut
Posting: # 13264
Views: 9,355

Unit conversions, F ≤1?

Post reply

Dear Helmut,
Thanks for the response. I have used winNonlin 6.3 version for PK calculations.
(Reference article values of Vd and CL) The pharmacokinetic parameters of total amphotericin B (mean ± SD) after the first dose and at steady state are shown in the table below.

[image]

I used dosing information in winNonlin i.e., 219 000 ug instead of 219 mg. In the NCA- setup select Normalization and kg is worked, I found unit correctly but still Cl and Vd values were not matches with reference article. After dose conversions I got same results

WinNonlin result of Vd and Cl is as below:

Subject Period VZ (mL/kg) CL(ml/hr/Kg)

   1      1     29759.19    833.39545

   1      2     82120.74   1029.7594

Reference: Prescribing information of AmBisome® (amphotericin B) liposome for injection from Astellas Pharma US, Inc. [cited 18 December, 2013]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050740s021lbl.pdf

[image]

Regards

—
Kumar Naidu

SDavis
★★

UK,
2014-07-16 08:49
(3932 d 12:34 ago)

@ kumarnaidu
Posting: # 13270
Views: 9,232

Unit conversions, F ≤1?

Post reply

Dear Kumar,

Can you not post the whole PHXPROJ and then we can see easily how you have set things up ?

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 two individual results without it being clear to me at what dose level/status.

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.

Simon.

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kumarnaidu
★

Mumbai, India,
2014-07-21 13:01
(3927 d 08:22 ago)

@ SDavis
Posting: # 13282
Views: 9,091

Unit conversions, F ≤1?

Post reply

Hello Simon,
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.

Also I have the PHXPROJ file but I dont know how to attach file here. Can I send it to you by email.

—
Kumar Naidu

Helmut
★★★

Vienna, Austria,
2014-07-21 15:57
(3927 d 05:26 ago)

@ kumarnaidu
Posting: # 13283
Views: 9,086

Avoid cross-posting

Post reply

Hi Kumar,

❝ Also I have the PHXPROJ file but I dont know how to attach file here.

You posted already at the Extranet. Try to keep the discussion in one place. You can upload your PHX project-file there.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes