Ignite Creation Date:
2024-05-05 @ 11:59 AM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00200798
Status:
COMPLETED
Last Update Posted:
2018-07-17
First Post:
2005-09-13
Brief Title:
An Assessment of Milk Thistle Pharmacokinetics and Drug Interactions
Sponsor:
Medical University of South Carolina
Organization:
Medical University of South Carolina
Study Overview
Official Title:
Pharmacokinetics and Drug Interactions With Milk Thistle
Status:
COMPLETED
Status Verified Date:
2018-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
There is accumulating evidence from various sources that extracts from the milk thistle plant can be useful in the treatment of a variety of liver ailments as well as other disorders This investigation will essentially be composed of two individual normal volunteer studies of milk thistle The first study will assess the rate and extent of absorption of components of a standardized botanical extract obtained from the milk thistle plant This first study is termed a bioavailability study This investigation will take approximately 8 weeks and involve 10 clinic visits Secondly a drug interaction study will be performed This is an assessment study of the potential for this botanical extract to interact with other prescription or over-the-counter medications This study is also expected to take approximately 8 weeks but will involve 18 clinic visits In both studies all subjects will receive the same milk thistle supplement and no placebo will be administered
Detailed Description:
BIOAVAILABILTY STUDY
1 Clinical Protocol
ScreeningInformed Consent Sixteen subjects will be recruited for the clinical protocol All protocols consent forms and HIPAA forms shall be IRB-approved prior to initiating any study procedure or recruitment At a screeninginformed consent visit the study design purposes and inclusionexclusion criteria will be explained to each prospective subject Written informed consent will be obtained prior to commencing any study procedures After informed consent is obtained medical examinations will be performed along with baseline serum chemistries complete blood count electrocardiogram urinalysis urine drug screen nicotinecotinine and urine pregnancy test females Subjects will be asked about their diets including alcohol use and the use of herbal medicationsdietary supplements If a potential subject has been consuming any herbal or dietary supplements a two-week period of abstinence from supplement use will be necessary before beginning the study Additionally subjects will refrain from use of honey or propolis-containing products due to presence of chrysin and potential assay interference and artichokes or artichoke-containing foods that also contain taxifolin a constituent found in MT
Single- and Multiple-Dose Silymarin Pharmacokinetics Subjects will arrive at the MUSC GCRC in the morning where they will remain for approximately 10-hours for each of 4 separate blood drawing phases of the study After checking in and under medical supervision a modification of a modified Treatment Emergent Symptoms Scale TESS will be administered and a registered nurse will place an indwelling venous catheter in each subjects arm to facilitate serial blood sampling At 8 AM after urinary void and collection of an aliquot for creatinine analysis subjects will take one 175 mg capsule of MT standardized to 80 SM 140 mg of SM The rationale for product choice is discussed below Subjects will be in a fasted state for 4 hours following MT administration to reduce any effect of food on absorption A total of 12 blood samples 10 ml each will be taken over the next 24-hour period All samples will be drawn in heparinized tubes and stored on ice until centrifugation at 4C As flavonoids are notorious for their instability in biological matrices no sample will remain on ice for longer than 15 minutes prior to centrifugation Time points of blood collection will be immediately prior to the dose of MT 0 time point and at 05 hours 10 15 20 30 40 60 80 12 and 24 hours A second TESS will be administered to the subjects 2 hours post-dosing at a time generally expected to represent silybin Cmax Subjects will be asked to return for 4 brief visits for collection of single blood samples through a separate venipuncture at time points of 24 36 and 48 hours This extended sampling will provide adequate PK data to determine Cmax AUC terminal t12 and Clo of SM flavonoids Standard meals will be served by the registered dietician at the GCRC and will not include any other sources of flavonoids The composition and amount of food eaten throughout the day will be recorded Plasma will be acidified with 10 ml of 1M acetic acidml plasma and frozen immediately at -70C This single dose assessment of silymarin pharmacokinetics will be conducted at three dosage levels of MT supplement in an attempt to span the usual therapeutic range of MT and will be performed on three distinct occasions separated by no less than a 7-day wash-out period The doses of MT used will be 175 mg 350 mg and 525 mg administered orally with 200 mL of water as one two and three capsules respectively Again these doses as well as product could be changed if a more standardized supplement is made available through NIHNCCAM or some other source The highest dose of MT supplement proposed for oral administration 525 mg 420 mg SM does not pose any undue risk to subjects since SM doses of 420 mg to 800 mg has been administered to many patients with hepatic dysfunction in clinical trials with few side effects reported NLM 2000 Saller et al 2001
Following the last single dose assessment and an ensuing 7-day minimum wash-out period subjects will initiate treatment of a 28-day treatment exposure to the MT supplement 175 mg 140 mg SM at the generally recommended and clinically studied dosage of one capsule thrice daily NLM 2000 A 28-day course is selected to assure steady-state is reached and to surpass the duration of any other published pharmacokinetic studies of SM in human subjects which have generally been of brief duration In addition this extended dosing assessment will allow for the gathering of pilot data on the antioxidant potential of SM via measurements of urinary isoprostanes Finally an assessment of treatment-emergent adverse effects and tolerability will be made Subjects will report to the outpatient GCRC on 4 separate occasions to pick up a 7-day supply of SM at which time a TESS will be administered At the initial visit to the GCRC to obtain the first weeks supply of MT subjects will provide a urine sample for baseline measurement of urinary isoprostanes and creatinine After 28 days of treatment subjects will report to the GCRC for the determination of steady-state concentrations of SMs in plasma and urine A blood draw will be performed immediately prior to dosing with the MT Ctrough and 05 10 20 30 and 40 and 80 following MT dosing Based upon available published data these timepoints should be sufficient to capture the Cmax for all flavonoids of interest despite interindividual variability Additionally subjects will provide a morning urine sample for analysis of urinary isoprostane and creatinine
Follow-Up Subjects will return 7 days following the final blood draw to have a follow-up serum chemistry and complete blood count CBC performed to provide an additional assurance of subject safety We will also perform a final assessment of adverse events using the TESS scale
DRUG INTERACTION ASSESSMENT
1 Clinical Protocol for Drug Interaction Assessment
An outline of the proposed clinical study to determine the drug interaction potential of silymarin
Assessing Cytochrome P450 Activity in vivo with Probe Drugs
Probe substrate compounds for the major CYP enzymes are available to assess genetic environmental and ethnic differences in enzyme activity In the last 2 years our research group has published 7 full research reports utilizing probe drug methodology in assessing botanical-drug interactions These studies were likewise funded by NCCAM had an excellent safety record and were performed within the MUSC GCRC
Probe compounds can be initially administered to subjects in the absence of suspected enzyme inhibitors or inducers and the parent drug or drug metabolite ratios measured in plasma and urine to reflect enzyme activity This assessment can then be repeated in the presence of a suspected inhibitor or inducer and comparisons can be made In this manner specific enzyme inhibitory or inductive effects can be elucidated documented and generalized to other similar substrates In this study by using the selected probe substrates alprazolam CYP3A4 dextromethorphan CYP2D6 tolbutamide TOL CYP2C9 and caffeine CYP1A2 we will assess the ability of MTSM to selectively alter one or more of the major drug metabolizing enzymes responsible for the metabolism of 80 of all therapeutically used drugs
We propose to use these validated and widely accepted methods to evaluate the drug-interaction potential of a characterized MT supplement A clinical protocol using 16 normal volunteers will evaluate the potential to inhibit or induce CYP3A4 CYP1A2 CYP2C9 and the potential to inhibit CYP2D6 a non-inducible isoform Test doses of these four safe probe drugs will be administered at baseline before treatment with MT and after a 14-day treatment period Changes in the pharmacokinetics of these probe drugs will indicate the degree of specific enzyme inhibition or induction respectively These data will be used to evaluate the effects of combining a standardized MT supplement with other drugs that are substrates for the CYP enzymes studied
ScreeningInformed Consent Sixteen subjects will be recruited for the clinical protocol and replacements will be recruited if necessary for 16 subjects to complete the protocol Screening and a separate informed consent process will take place as in the pharmacokinetic study previously described with the following exceptions Subjects will be genotyped to determine if they are poor metabolizers of CYP2D6 substrates Subjects will also be asked about adverse events according to a Treatment Emergent Symptoms Scale TESS Zhang et al 2001 to determine if any symptoms are present prior to administration of the MT supplement Subjects will be asked about their diets including alcohol use and the use of herbal medicationsdietary supplements If a potential subject has been consuming any herbal or dietary supplements a two week period of abstinence from supplement use will be necessary before beginning the next study phase
Baseline CYP profile Subjects will return to the GCRC at a specified time in the morning prior to probe drug administration In the morning an indwelling venous catheter will be placed in each subjects arm to facilitate serial blood sampling At 8AM after urinary void subjects will be asked to take simultaneous single oral doses of 2 mg ALPZ 100 mg CAF 100 mg TOL and 30 mg DM At this time a urine collection will commence for the first eight hours of the visit A total of 11 blood samples 10 ml each will be taken over a 12-hour period Time points of blood collection will be immediately before drug administration and at 05 hours 10 15 20 30 40 60 80 and 12 hours Additionally the subjects will be asked to return for 4 more brief visits for collection of single blood samples through a separate venipuncture at time points of 24 36 and 48 hours This extended sampling will provide adequate pharmacokinetic data to determine Cmax AUC terminal t12 and Clo of all probe drugs To reduce any potential variability in drug absorption due to food the subjects will be in a fasted state for 4 hours following probe drug administration Standard meals will be served by the registered dietician at the GCRC and will not include grapefruit artichoke products or CAF The composition and amount of food eaten throughout the day will be recorded
MT Treatment Period Subjects will commence treatment with the MT supplement 175 mg 140 mg SM one capsule three times daily 8AM 12 noon 8PM for a period of 14 days Subjects will be supplied with pre-loaded medication organizers containing the daily doses of MT to promote compliance with the regimen Subjects will be asked to return to the study site for 4 pre-scheduled appointments during this time for capsule counts to discuss compliance with dietary restrictions and for monitoring of adverse events
Post-MT CYP profile Subjects will return to the GCRC for this phase of the study Subjects will check in the morning prior to a repeat dosing of probe medications The profiling of CYP3A4 CYP2D6 and CYP1A2 will be performed exactly as described for the baseline phase with the exception that for the first 24 hours subjects will continue their previous schedules of dosing with the MT supplement The doses of probe drugs will coincide with the 8AM dose of MT so that they will be taken concomitantly Blood and urine sampling times will be identical As in the baseline phase subjects will be in a fasted state for 4 hours following probe drug administration Additionally subjects will be served identical meals at the same timepoints as in the baseline phase
Follow-Up Subjects will return 7 days following the final blood draw to have a follow-up serum chemistry and complete blood count CBC performed to provide an additional assurance of subject safety We will also perform a final assessment of adverse events using the TESS scale
Probe Drugs Alprazolam ALPZ dextromethorphan DM tolbutamide TOL and caffeine CAF
1 Clinical Protocol
ScreeningInformed Consent Sixteen subjects will be recruited for the clinical protocol All protocols consent forms and HIPAA forms shall be IRB-approved prior to initiating any study procedure or recruitment At a screeninginformed consent visit the study design purposes and inclusionexclusion criteria will be explained to each prospective subject Written informed consent will be obtained prior to commencing any study procedures After informed consent is obtained medical examinations will be performed along with baseline serum chemistries complete blood count electrocardiogram urinalysis urine drug screen nicotinecotinine and urine pregnancy test females Subjects will be asked about their diets including alcohol use and the use of herbal medicationsdietary supplements If a potential subject has been consuming any herbal or dietary supplements a two-week period of abstinence from supplement use will be necessary before beginning the study Additionally subjects will refrain from use of honey or propolis-containing products due to presence of chrysin and potential assay interference and artichokes or artichoke-containing foods that also contain taxifolin a constituent found in MT
Single- and Multiple-Dose Silymarin Pharmacokinetics Subjects will arrive at the MUSC GCRC in the morning where they will remain for approximately 10-hours for each of 4 separate blood drawing phases of the study After checking in and under medical supervision a modification of a modified Treatment Emergent Symptoms Scale TESS will be administered and a registered nurse will place an indwelling venous catheter in each subjects arm to facilitate serial blood sampling At 8 AM after urinary void and collection of an aliquot for creatinine analysis subjects will take one 175 mg capsule of MT standardized to 80 SM 140 mg of SM The rationale for product choice is discussed below Subjects will be in a fasted state for 4 hours following MT administration to reduce any effect of food on absorption A total of 12 blood samples 10 ml each will be taken over the next 24-hour period All samples will be drawn in heparinized tubes and stored on ice until centrifugation at 4C As flavonoids are notorious for their instability in biological matrices no sample will remain on ice for longer than 15 minutes prior to centrifugation Time points of blood collection will be immediately prior to the dose of MT 0 time point and at 05 hours 10 15 20 30 40 60 80 12 and 24 hours A second TESS will be administered to the subjects 2 hours post-dosing at a time generally expected to represent silybin Cmax Subjects will be asked to return for 4 brief visits for collection of single blood samples through a separate venipuncture at time points of 24 36 and 48 hours This extended sampling will provide adequate PK data to determine Cmax AUC terminal t12 and Clo of SM flavonoids Standard meals will be served by the registered dietician at the GCRC and will not include any other sources of flavonoids The composition and amount of food eaten throughout the day will be recorded Plasma will be acidified with 10 ml of 1M acetic acidml plasma and frozen immediately at -70C This single dose assessment of silymarin pharmacokinetics will be conducted at three dosage levels of MT supplement in an attempt to span the usual therapeutic range of MT and will be performed on three distinct occasions separated by no less than a 7-day wash-out period The doses of MT used will be 175 mg 350 mg and 525 mg administered orally with 200 mL of water as one two and three capsules respectively Again these doses as well as product could be changed if a more standardized supplement is made available through NIHNCCAM or some other source The highest dose of MT supplement proposed for oral administration 525 mg 420 mg SM does not pose any undue risk to subjects since SM doses of 420 mg to 800 mg has been administered to many patients with hepatic dysfunction in clinical trials with few side effects reported NLM 2000 Saller et al 2001
Following the last single dose assessment and an ensuing 7-day minimum wash-out period subjects will initiate treatment of a 28-day treatment exposure to the MT supplement 175 mg 140 mg SM at the generally recommended and clinically studied dosage of one capsule thrice daily NLM 2000 A 28-day course is selected to assure steady-state is reached and to surpass the duration of any other published pharmacokinetic studies of SM in human subjects which have generally been of brief duration In addition this extended dosing assessment will allow for the gathering of pilot data on the antioxidant potential of SM via measurements of urinary isoprostanes Finally an assessment of treatment-emergent adverse effects and tolerability will be made Subjects will report to the outpatient GCRC on 4 separate occasions to pick up a 7-day supply of SM at which time a TESS will be administered At the initial visit to the GCRC to obtain the first weeks supply of MT subjects will provide a urine sample for baseline measurement of urinary isoprostanes and creatinine After 28 days of treatment subjects will report to the GCRC for the determination of steady-state concentrations of SMs in plasma and urine A blood draw will be performed immediately prior to dosing with the MT Ctrough and 05 10 20 30 and 40 and 80 following MT dosing Based upon available published data these timepoints should be sufficient to capture the Cmax for all flavonoids of interest despite interindividual variability Additionally subjects will provide a morning urine sample for analysis of urinary isoprostane and creatinine
Follow-Up Subjects will return 7 days following the final blood draw to have a follow-up serum chemistry and complete blood count CBC performed to provide an additional assurance of subject safety We will also perform a final assessment of adverse events using the TESS scale
DRUG INTERACTION ASSESSMENT
1 Clinical Protocol for Drug Interaction Assessment
An outline of the proposed clinical study to determine the drug interaction potential of silymarin
Assessing Cytochrome P450 Activity in vivo with Probe Drugs
Probe substrate compounds for the major CYP enzymes are available to assess genetic environmental and ethnic differences in enzyme activity In the last 2 years our research group has published 7 full research reports utilizing probe drug methodology in assessing botanical-drug interactions These studies were likewise funded by NCCAM had an excellent safety record and were performed within the MUSC GCRC
Probe compounds can be initially administered to subjects in the absence of suspected enzyme inhibitors or inducers and the parent drug or drug metabolite ratios measured in plasma and urine to reflect enzyme activity This assessment can then be repeated in the presence of a suspected inhibitor or inducer and comparisons can be made In this manner specific enzyme inhibitory or inductive effects can be elucidated documented and generalized to other similar substrates In this study by using the selected probe substrates alprazolam CYP3A4 dextromethorphan CYP2D6 tolbutamide TOL CYP2C9 and caffeine CYP1A2 we will assess the ability of MTSM to selectively alter one or more of the major drug metabolizing enzymes responsible for the metabolism of 80 of all therapeutically used drugs
We propose to use these validated and widely accepted methods to evaluate the drug-interaction potential of a characterized MT supplement A clinical protocol using 16 normal volunteers will evaluate the potential to inhibit or induce CYP3A4 CYP1A2 CYP2C9 and the potential to inhibit CYP2D6 a non-inducible isoform Test doses of these four safe probe drugs will be administered at baseline before treatment with MT and after a 14-day treatment period Changes in the pharmacokinetics of these probe drugs will indicate the degree of specific enzyme inhibition or induction respectively These data will be used to evaluate the effects of combining a standardized MT supplement with other drugs that are substrates for the CYP enzymes studied
ScreeningInformed Consent Sixteen subjects will be recruited for the clinical protocol and replacements will be recruited if necessary for 16 subjects to complete the protocol Screening and a separate informed consent process will take place as in the pharmacokinetic study previously described with the following exceptions Subjects will be genotyped to determine if they are poor metabolizers of CYP2D6 substrates Subjects will also be asked about adverse events according to a Treatment Emergent Symptoms Scale TESS Zhang et al 2001 to determine if any symptoms are present prior to administration of the MT supplement Subjects will be asked about their diets including alcohol use and the use of herbal medicationsdietary supplements If a potential subject has been consuming any herbal or dietary supplements a two week period of abstinence from supplement use will be necessary before beginning the next study phase
Baseline CYP profile Subjects will return to the GCRC at a specified time in the morning prior to probe drug administration In the morning an indwelling venous catheter will be placed in each subjects arm to facilitate serial blood sampling At 8AM after urinary void subjects will be asked to take simultaneous single oral doses of 2 mg ALPZ 100 mg CAF 100 mg TOL and 30 mg DM At this time a urine collection will commence for the first eight hours of the visit A total of 11 blood samples 10 ml each will be taken over a 12-hour period Time points of blood collection will be immediately before drug administration and at 05 hours 10 15 20 30 40 60 80 and 12 hours Additionally the subjects will be asked to return for 4 more brief visits for collection of single blood samples through a separate venipuncture at time points of 24 36 and 48 hours This extended sampling will provide adequate pharmacokinetic data to determine Cmax AUC terminal t12 and Clo of all probe drugs To reduce any potential variability in drug absorption due to food the subjects will be in a fasted state for 4 hours following probe drug administration Standard meals will be served by the registered dietician at the GCRC and will not include grapefruit artichoke products or CAF The composition and amount of food eaten throughout the day will be recorded
MT Treatment Period Subjects will commence treatment with the MT supplement 175 mg 140 mg SM one capsule three times daily 8AM 12 noon 8PM for a period of 14 days Subjects will be supplied with pre-loaded medication organizers containing the daily doses of MT to promote compliance with the regimen Subjects will be asked to return to the study site for 4 pre-scheduled appointments during this time for capsule counts to discuss compliance with dietary restrictions and for monitoring of adverse events
Post-MT CYP profile Subjects will return to the GCRC for this phase of the study Subjects will check in the morning prior to a repeat dosing of probe medications The profiling of CYP3A4 CYP2D6 and CYP1A2 will be performed exactly as described for the baseline phase with the exception that for the first 24 hours subjects will continue their previous schedules of dosing with the MT supplement The doses of probe drugs will coincide with the 8AM dose of MT so that they will be taken concomitantly Blood and urine sampling times will be identical As in the baseline phase subjects will be in a fasted state for 4 hours following probe drug administration Additionally subjects will be served identical meals at the same timepoints as in the baseline phase
Follow-Up Subjects will return 7 days following the final blood draw to have a follow-up serum chemistry and complete blood count CBC performed to provide an additional assurance of subject safety We will also perform a final assessment of adverse events using the TESS scale
Probe Drugs Alprazolam ALPZ dextromethorphan DM tolbutamide TOL and caffeine CAF
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R21AT002817-01 | NIH | None | httpsreporternihgovquickSearchR21AT002817-01 |