Wise Young
07-03-2006, 07:39 AM
It is well known that very high doses of gabapentin must be given to people for neuropathic pain. Some people require as much as 4-5 grams per day of the drug and the dose required seems to increase over time. Since 1993, scientists have known that gabapentin shows saturable absorption kinetics. In other words, it is transported into the body by an amino-acid transport system that saturates at high doses. This study from the Population Approach Group Meeting in Pamplona Spain in 2005 confirms that gabapentin in high doses is not being absorbed as well. This also explains why such high doses do not produce more side-effect.
Poster pdf (http://www.page-meeting.org/page/page2005/PAGE2005P68.pdf)
http://www.page-meeting.org/default.asp?abstract=777
PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032
Reference:
PAGE 14 (2005) Abstr 777 [www.page-meeting.org/?abstract=777]
Bioavailability of gabapentin assessed by cumulative urine sampling compared with a model for the saturated absorption of gabapentin.
K.C. Carlsson(1), M. Bergjord(1), E.R. Moberg(2) and N.O. Hoem(1)
(1) Department of Pharmacology, School of Pharmacy, University of Oslo, Norway, (2) Institute of Pharmacology, Faculty of Medicine, University of Oslo, Norway.
Kristin Cecilie Carlsson
poster
PDF of poster
Introduction: Gabapentin has a demonstrated analgesic effect in patients with chronic neuropathic pain states 1 and is well established in the treatment of seizures. Gabapentin does not bind to plasma proteins and is excreted unchanged in the kidneys. Gabapentin displays dose dependent, saturable absorption. This is believed to include an active transport process mechanism by an L-amino acid transporter 2. This absorption pattern is believed to explain lack of effect in many patients due to sub-optimal dosing, but also low toxicity since high doses will be less absorbed 3.
Methods: Patients with chronic, neuropathic pain receiving gabapentin as their main pain treatment were included in the study. The subjects were monitored during one dose interval (6-8 h) when in steady state. The bladder was emptied before the gabapentin dose was taken. Total urine volumes were measured and gabapentin concentrations measured by LC/MS-MS 4. An estimate of excreted gabapentin pr 24 h were calculated based on the length of urine collection, urine volume and concentration of drug in the urine. An estimate for bioavailability estimated from urine collection (FU) was calculated by using the following formula:
FU = (amount excreted in urine in mg/24 h)/DD
where DD is daily dose of gabapentin. These estimates were compared to estimates found by using a model for gabapentin absorption developed by Gidal et al. 5 These authors report a Michaelis-Menten relationship between F and DD where the bioavailability estimated by the model (FM) was found to be:
FM = Dmax / (D50 + DD), Dmax = 2720 mg/day and D50 = 4080 mg/day.
Results: A good agreement was found between the two estimates of F. The model was able to predict an estimate of F close to the measured value in five out of seven patients. Average bioavailability for the seven patients was almost the same for model and urine collection, 42.5% and 43.7% respectively.
Conclusions: These results demonstrate that the absorption model can be included in pharmacokinetic models to be used in the monitoring of gabapentin.
References:
1. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. Jama. 1998;280:1837-1842.
2. Stewart BH, Kugler AR, Thompson PR, et al. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceutical Research. 1993;10:276-281.
3. McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy. Clinical Therapeutics. 2003;25:1382-1406.
4. Carlsson KC, Reubsaet JLE. Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2004;34:415-423.
5. Gidal BE, DeCerce J, Bockbrader HN, et al. Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy. Epilepsy Research. 1998;31:91-99.
In 2003, a group at the University of Oslo published a model that predicts the dosage requirements for gabapentin for the treatment of epilepsy and neuropathic pain. This model should be useful for predicting future dosage requirements of the drug.
http://www.page-meeting.org/default.asp?abstract=433
PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032
Reference:
PAGE 12 (2003) Abstr 433 [www.page-meeting.org/?abstract=433]
Establishing a tool for individualised dosing of gabapentin - The use of a non-parametric population kinetics model in the MM-USCPACK software, a new tool for clinical dosage optimization.
Kristin Cecilie Carlsson(1), Heidi Hansen(1), Roger Jelliffe(2), Nils Ove Hoem(3).
(1)Dept. of Pharmacology, School of Pharmacy, University of Oslo, Norway.(2) Laboratory of Applied Pharmacokinetics, University of Southern California, USA. (3) Smerud Medical Research, Oslo Norway.
Nils Ove Hoem
poster
To be able to use pharmacokinetic tools in clinical practice, they must be easily available to the physician at the clinic, or even bedside. To be clinically useful, even in many everyday situations, such tools must be able to handle relatively complex pharmacokinetic models, and also be able to take into account continuous changes in the patient’s condition.
The MM-USCPACK software employs an interacting multiple-model (non-parametric) strategy for analyzing previous serum concentration-time data and predicting future dosage regimens. The MM-USCPACK software can be used on a portable computer and have a jump function that makes it possible to handle continuously changing parameter estimates.
To facilitate individualized dosing of gabapentin, a population pharmacokinetic model has been developed consisting of an absorption and a central compartment, and with speed of elimination described as a linear function of creatinine clearance.
We have dose monitored a small number of patients who were treated with gabapentin against neuropathic pain (8 patients with a total of 19 dosage interval profiles).
Serum concentration levels, analgesic effects and adverse effects measured by a visual analog scale, were registered as time variables. The covariates gender, age, height, weight, serum creatinine and total daily dose were registered as patient characteristics.
The parameters for the pharmacokinetic model were first estimated by a parametric standard two-stage Bayesian population tool (IT2B) and then with the Non-Parametric Adaptive Grid (NPAG) tool recently developed by The Laboratory of Applied Pharmacokinetics. The resulting population pharmacokinetic model can together with the MM-USCPACK software be used to optimize dosing of gabapentin in the chosen patient population.
Poster pdf (http://www.page-meeting.org/page/page2005/PAGE2005P68.pdf)
http://www.page-meeting.org/default.asp?abstract=777
PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032
Reference:
PAGE 14 (2005) Abstr 777 [www.page-meeting.org/?abstract=777]
Bioavailability of gabapentin assessed by cumulative urine sampling compared with a model for the saturated absorption of gabapentin.
K.C. Carlsson(1), M. Bergjord(1), E.R. Moberg(2) and N.O. Hoem(1)
(1) Department of Pharmacology, School of Pharmacy, University of Oslo, Norway, (2) Institute of Pharmacology, Faculty of Medicine, University of Oslo, Norway.
Kristin Cecilie Carlsson
poster
PDF of poster
Introduction: Gabapentin has a demonstrated analgesic effect in patients with chronic neuropathic pain states 1 and is well established in the treatment of seizures. Gabapentin does not bind to plasma proteins and is excreted unchanged in the kidneys. Gabapentin displays dose dependent, saturable absorption. This is believed to include an active transport process mechanism by an L-amino acid transporter 2. This absorption pattern is believed to explain lack of effect in many patients due to sub-optimal dosing, but also low toxicity since high doses will be less absorbed 3.
Methods: Patients with chronic, neuropathic pain receiving gabapentin as their main pain treatment were included in the study. The subjects were monitored during one dose interval (6-8 h) when in steady state. The bladder was emptied before the gabapentin dose was taken. Total urine volumes were measured and gabapentin concentrations measured by LC/MS-MS 4. An estimate of excreted gabapentin pr 24 h were calculated based on the length of urine collection, urine volume and concentration of drug in the urine. An estimate for bioavailability estimated from urine collection (FU) was calculated by using the following formula:
FU = (amount excreted in urine in mg/24 h)/DD
where DD is daily dose of gabapentin. These estimates were compared to estimates found by using a model for gabapentin absorption developed by Gidal et al. 5 These authors report a Michaelis-Menten relationship between F and DD where the bioavailability estimated by the model (FM) was found to be:
FM = Dmax / (D50 + DD), Dmax = 2720 mg/day and D50 = 4080 mg/day.
Results: A good agreement was found between the two estimates of F. The model was able to predict an estimate of F close to the measured value in five out of seven patients. Average bioavailability for the seven patients was almost the same for model and urine collection, 42.5% and 43.7% respectively.
Conclusions: These results demonstrate that the absorption model can be included in pharmacokinetic models to be used in the monitoring of gabapentin.
References:
1. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. Jama. 1998;280:1837-1842.
2. Stewart BH, Kugler AR, Thompson PR, et al. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceutical Research. 1993;10:276-281.
3. McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy. Clinical Therapeutics. 2003;25:1382-1406.
4. Carlsson KC, Reubsaet JLE. Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2004;34:415-423.
5. Gidal BE, DeCerce J, Bockbrader HN, et al. Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy. Epilepsy Research. 1998;31:91-99.
In 2003, a group at the University of Oslo published a model that predicts the dosage requirements for gabapentin for the treatment of epilepsy and neuropathic pain. This model should be useful for predicting future dosage requirements of the drug.
http://www.page-meeting.org/default.asp?abstract=433
PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032
Reference:
PAGE 12 (2003) Abstr 433 [www.page-meeting.org/?abstract=433]
Establishing a tool for individualised dosing of gabapentin - The use of a non-parametric population kinetics model in the MM-USCPACK software, a new tool for clinical dosage optimization.
Kristin Cecilie Carlsson(1), Heidi Hansen(1), Roger Jelliffe(2), Nils Ove Hoem(3).
(1)Dept. of Pharmacology, School of Pharmacy, University of Oslo, Norway.(2) Laboratory of Applied Pharmacokinetics, University of Southern California, USA. (3) Smerud Medical Research, Oslo Norway.
Nils Ove Hoem
poster
To be able to use pharmacokinetic tools in clinical practice, they must be easily available to the physician at the clinic, or even bedside. To be clinically useful, even in many everyday situations, such tools must be able to handle relatively complex pharmacokinetic models, and also be able to take into account continuous changes in the patient’s condition.
The MM-USCPACK software employs an interacting multiple-model (non-parametric) strategy for analyzing previous serum concentration-time data and predicting future dosage regimens. The MM-USCPACK software can be used on a portable computer and have a jump function that makes it possible to handle continuously changing parameter estimates.
To facilitate individualized dosing of gabapentin, a population pharmacokinetic model has been developed consisting of an absorption and a central compartment, and with speed of elimination described as a linear function of creatinine clearance.
We have dose monitored a small number of patients who were treated with gabapentin against neuropathic pain (8 patients with a total of 19 dosage interval profiles).
Serum concentration levels, analgesic effects and adverse effects measured by a visual analog scale, were registered as time variables. The covariates gender, age, height, weight, serum creatinine and total daily dose were registered as patient characteristics.
The parameters for the pharmacokinetic model were first estimated by a parametric standard two-stage Bayesian population tool (IT2B) and then with the Non-Parametric Adaptive Grid (NPAG) tool recently developed by The Laboratory of Applied Pharmacokinetics. The resulting population pharmacokinetic model can together with the MM-USCPACK software be used to optimize dosing of gabapentin in the chosen patient population.