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Lena ☆ Ukraine, 2012-06-07 17:32 (5119 d 22:46 ago) Posting: # 8672 Views: 7,151 |
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Hello! We got the data from our pilot clinical trials: data sets of plasma concentration for: 1) IV bolus 1000 mg (female); 2) IR tablets 500 mg (2 times/day, 0-12, 12-24, steady state 14 days, male); 3) CR tablets 1000 mg (once a day, steady state 14 days, male); 4) CR tablets 1000 mg (steady state 5 days, female). The data are very inconsistent. Can WinNonlin help me to understand the behavior of our drug? I mean, perhaps I can get any model or any calculations to understand where the active substance is absorbed. Thank you. |
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Helmut ★★★   Vienna, Austria, 2012-06-07 18:15 (5119 d 22:02 ago) @ Lena Posting: # 8674 Views: 6,038 |
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Dear Lena! ❝ We got the data from our pilot clinical trials: data sets of plasma concentration for: ❝ 1) IV bolus 1000 mg (female); ❝ 2) IR tablets 500 mg (2 times/day, 0-12, 12-24, steady state 14 days, male); ❝ 3) CR tablets 1000 mg (once a day, steady state 14 days, male); ❝ 4) CR tablets 1000 mg (steady state 5 days, female). ❝ The data are very inconsistent. Inconsistent in which respect – can you give us more information? Do you have so called ‘rich datasets’ (frequent sampling at least on profile days) or ‘sparse data’ (just a few samples per subject)? In the former case I would start with NCA in order to get preliminary estimates of PK metrics (AUC, V/F, λz, tlag,…). In the latter case WinNonlin offers a sparse sample NCA option. You can use these estimates as initial estimates in a PK model. You will get more insight on the behavior of the drug if you try to fit a Population PK model. There you can include covariates (body weight/surface area, sex, creatinine clearance for renaly excreted unchanged drugs, …). Generally you start with the same model as in ‘classical’ PK and subsequently add covariates until the explained variance does not improve any more. Involves a lot of trial-and-error; patience mandatory. ❝ Can WinNonlin help me … Which version of WinNonlin do you have? If you have one of the classical versions of WinNonlin I would strongly suggest to update to Phoenix for free as soon as possible. Much easier there. I would also recommend to register at Pharsight’s Extranet. There you can even post your datasets and might get help in setting up models by Pharsight’s staff and experienced users. ❝ … to understand the behavior of our drug? I mean, perhaps I can get any model or any calculations to understand where the active substance is absorbed. Models tell you little about the site(s) of absorption. You have to know your API and formulation: ionisation state (absorption window), enteric coating (tlag), release properties of the CR (zero order resulting in flip-flop PK: ka < kel)… — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Lena ☆ Ukraine, 2012-06-07 18:54 (5119 d 21:23 ago) @ Helmut Posting: # 8675 Views: 6,041 |
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Dear Helmut! Thank you for your reply. ❝ Inconsistent in which respect – can you give us more information? Do you have so called ‘rich datasets’ (frequent sampling at least on profile days) or ‘sparse data’ (just a few samples per subject)? In the former case I would start with NCA in order to get preliminary estimates of PK metrics (AUC, V/F, λz, tlag,…). I think we have ‘rich datasets’ . I got NCA for each data set. We expected to get the same AUCs for IR 500 mg tablets (2 times/day) and CR 1000 mg tablets (once a day). But AUC of CR is much less then AUC of IR. ❝ You will get more insight on the behavior of the drug if you try to fit a Population PK model. There you can include covariates (body weight/surface area, sex, creatinine clearance for renaly excreted unchanged drugs, …). Generally you start with the same model as in ‘classical’ PK and subsequently add covariates until the explained variance does not improve any more. I'll try. ❝ Which version of WinNonlin do you have? If you have one of the classical versions of WinNonlin I would strongly suggest to update to Phoenix for free as soon as possible. Much easier there. ❝ I would also recommend to register at Pharsight’s Extranet. There you can even post your datasets and might get help in setting up models by Pharsight’s staff and experienced users. I have WNL 6.3.0. I have posted the post with WNL project on Pharsight’s Extranet. Please have a look. ❝ Models tell you little about the site(s) of absorption. You have to know your API and formulation: ionisation state (absorption window), enteric coating (tlag), release properties of the CR (zero order resulting in flip-flop PK: ka < kel)… Now I have to understand if we got not good formulation or the active substance doesn't absorbed with higher pH. Best wishes, Lena |
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jag009 ★★★ NJ, 2012-06-08 18:09 (5118 d 22:08 ago) @ Lena Posting: # 8681 Views: 5,949 |
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Hi Lana, I assume you are comparing AUC IR bid vs AUC CR in males. Questions
Hope this helps. |
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Lena ☆ Ukraine, 2012-06-14 17:16 (5112 d 23:01 ago) @ jag009 Posting: # 8738 Views: 5,839 |
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Hi jag009! ❝ I assume you are comparing AUC IR bid vs AUC CR in males. Yes, you are right. I need to compare IR tablets 500 mg (2 times/day) and CR tablets 1000 mg (once a day). ❝ 1. Are the trough levels (or concentration at time 0 or time 24) between the IR bid and CR q.d. at steady state similar? No. After steady state 14 days Cmin of IR tabl is 2600 ng/ml, Cmin of CR tabl is 1000 ng/ml. Tmax is 5 hours for both. The time-concentration profile has double peak. Does it mean that CR tabl has specific absorption sites? Thank you. |
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