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Clinical Utility of Monitoring Tacrolimus
Blood Concentrations in Liver
Transplant Patients
Raman Venkataramanan, PhD, Leslie M. Shaw, PhD, Laszlo Sarkozi, PhD, Richard Mullins, PhD, John Pirsch, MD, Gordon MacFarlane, PhD, Dan Scheller, BS, Diana Ersfeld, BA, Mary Frick, MS, William E. Fitzsimmons, PharmD, Mohammed Virji, MD, Ashok Jain, MD, Kenneth L. Brayman, MD, and Abraham Shaked, MD The relationship between the dose of tacrolimus, trough creasing risk of acute rejection was demonstrated over a tacrolimus blood concentration, and selected clinical end- 7-day time window. Nephrotoxicity and other toxicities also points (acute rejection, nephrotoxicity, and other toxicities) demonstrated statistically significant relationships with were examined in a prospective, multicenter clinical trial to trough tacrolimus blood concentrations. The results of the validate the use of an enzyme-linked immunosorbent assay Cox analysis were consistent with the logistic regression (ELISA) for monitoring whole-blood concentrations of analysis. Using receiver operator characteristic curves, tacrolimus in liver transplant patients. A total of 111 subjects trough tacrolimus concentrations as measured by the ELISA from six transplant centers were evaluated over 12 weeks method were able to differentiate the occurrence of posttransplantation. In addition to trough tacrolimus blood nephrotoxicity and toxicity from nonevents. To minimize concentrations, hematocrit, ALT, AST, GGTP, alkaline nephrotoxicity of tacrolimus, it is necessary to maintain phosphatase, total bilirubin, serum creatinine, BUN, serum trough blood concentrations below 15 ng/ml. This study potassium, serum magnesium, blood glucose, and serum al- demonstrates that the ELISA method used to measure bumin were also measured. The relationship between trough tacrolimus blood concentrations in this study provides in- tacrolimus blood concentrations and clinical endpoints was formation of predictive value for managing the risk of analyzed using both a logistic regression model and a Cox nephrotoxicity, other toxicity, and rejection in liver trans- proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between in- Journal of Clinical Pharmacology, 2001;41:542-551
creasing trough tacrolimus blood concentrations and de- 2001 the American College of Clinical Pharmacology
From the Department of Pharmaceutical Sciences, Pathology, and Surgery,University of Pittsburgh, Pennsylvania (Dr. Venkataramanan, Dr. Virji, Dr.
The contribution of tacrolimus to effective
immunosuppression in the field of organ trans- Jain); the Department of Clinical Chemistry and Surgery, University of plantation is well established.1-4 While tacrolimus is a Pennsylvania Medical Center, Philadelphia (Dr. Shaw, Dr. Brayman, Dr.
potent immunosuppressive drug, it has a narrow thera- Shaked); the Department of Clinical Chemistry, Mt. Sinai Medical Center, peutic index.5-7 The large interindividual variation in New York (Dr. Sarkozi); the Department of Clinical Chemistry, Emory Uni- the pharmacokinetics of tacrolimus necessitates indi- versity, Atlanta, Georgia (Dr. Mullins); Department of Clinical Chemistry, vidualization of the dosing regimen of tacrolimus in University of Wisconsin Hospital and Clinics, Madison, Wisconsin (Dr.
transplant patients.8-10 In addition, to achieve long-term Pirsch); DiaSorin, Inc., Stillwater, Minnesota (Dr. MacFarlane, Mr. Scheller, graft survival, it is essential that the patients are com- Ms. Frick, Ms. Ersfeld); and Fujisawa Healthcare, Inc., Deerfield, Illinois pliant with the prescribed dosing regimen. Optimiza- (Dr. Fitzsimmons). This work was supported by DiaSorin, Inc., Stillwater, tion of tacrolimus therapy in organ transplant patients Minnesota. Submitted for publication August 16, 2000; revised versionaccepted October 26, 2000. Address for reprints: Raman Venkatara- currently uses routine tacrolimus trough-level moni- manan, PhD, FCP, Professor of Pharmaceutical Sciences and Pathology, toring as an integral component.11-12 One of the funda- University of Pittsburgh, Pittsburgh, PA 15261.
mental premises in the application of therapeutic drug 542 · J Clin Pharmacol 2001;41:542-551
MONITORING TACROLIMUS BLOOD CONCENTRATIONS monitoring is the documentation of a relationship be- small as 92 subjects.19 In addition, the difference in the tween the blood concentrations of a drug and its effi- incidence of toxicity was shown to be 20% to 30% cacy or toxicity. While there have been several causal when subjects with high concentrations of tacrolimus observations of association of rejection at lower con- were compared with subjects with low concentrations centrations and toxicity at higher concentrations of of tacrolimus. Assuming a between-group difference of tacrolimus,13-18 there has been only one thorough retro- 25% and a toxicity rate of 35% in the low concentration spective analysis of the relationship between tacro- group, a sample size of 94 subjects would be required to limus blood concentrations and efficacy and toxicity in detect such a difference, assuming α = 0.05 (one-sided) transplant patients.19 In addition, the methods avail- able to monitor tacrolimus concentrations differ partic- Tacrolimus was given intravenously for the first few ularly with respect to analytical sensitivity.20-23 The pri- days after transplantation in two centers. Tacrolimus mary goal of the current study was to prospectively was given orally to all the subjects in other centers. Ad- evaluate the relationship between tacrolimus blood justments in the dose of tacrolimus were made on the concentrations, as determined by an enzyme-linked basis of the standard of care at each center and included immunosorbent assay (ELISA), and the risk of rejection blood level monitoring of tacrolimus20 and other clini- and toxicity in liver transplant patients in a multicenter cal indices such as serum bilirubin, alkaline phos- PATIENTS AND METHODS
Data Collection
Patient Population
Baseline characteristics that included demographics,medical history, and clinical laboratory values were In the present prospective study, we enrolled 111 adult collected from all the subjects. Subjects were evaluated liver transplant subjects between August 1996 and July for 12 weeks posttransplantation. Morning trough 1997 at six clinical sites in the United States. These tacrolimus concentrations (collected before the morn- sites were the following: University of Pittsburgh Medi- ing dose) and clinical laboratory measurements that in- cal Center, Pittsburgh; University of Pennsylvania cluded ALT, AST, alkaline phosphatase, GGTP, total Medical Center, Philadelphia; Mt. Sinai Medical Cen- bilirubin, serum creatinine, BUN, serum potassium, se- ter, New York; Emory University, Atlanta, Georgia; Uni- rum magnesium, blood glucose, albumin, and hema- versity of Miami Medical School and VA Medical Cen- tocrit were measured three times a week during weeks ter, Miami, Florida; and University of Wisconsin 1 and 2, twice a week during weeks 3 and 4, once a Hospitals and Clinics, Madison. The study protocol week during weeks 5 and 6, and once every 2 weeks was approved by the institutional review board at each site. The study population was restricted to subjects re- Tacrolimus trough concentrations were assayed in ceiving tacrolimus as a primary immunosuppressant whole blood by PRO-Trac™ II ELISA.21,22 Venous blood following liver transplantation. Subjects receiving a was collected in 5 or 10 mL evacuated glass tubes con- liver from an ABO incompatible donor, subjects who taining EDTA or heparin as the anticoagulant. No fur- had prior organ transplantation other than the liver, or ther additive or preservative was required to maintain subjects who underwent transplantation of other or- the integrity of the samples. Specimens not processed gans at the time of liver transplantation were excluded immediately were stored at –18°C to –25°C and ana- from the study. Subjects were on a combination of lyzed within 7 days. Under this storage condition, tacrolimus, steroid, and azathioprine or mycopheno- tacrolimus has been shown to be stable.22 late mofetil. Subjects did not receive any investiga- Subjects were monitored for three primary end- tional immunosuppressant, with the exception of points: acute rejection confirmed by histology, nephro- mycophenolate mofetil. Informed consent for partici- toxicity defined as a serum creatinine elevation to pation in the study was obtained from the subject or the greater than two times the baseline value, and evidence subject’s authorized legal representative prior to enroll- of toxicity defined as any adverse event that required a reduction in dose of tacrolimus. In addition, two sec- The sample size estimation for the study was based ondary endpoints, death and retransplantation due to on previous logistic and Cox regression analyses of graft failure, were also monitored. Parameters calcu- clinical trials in which tacrolimus blood levels were lated included time to endpoint (days from transplant correlated positively with toxicity in populations as to endpoint), tacrolimus trough level 0 to 7 days prior to that endpoint, lowest tacrolimus trough within the The clinical sensitivity and specificity were calculated time window for rejection, and highest tacrolimus for rejection, toxicity, and nephrotoxicity using re- trough within the time window for all other endpoints.
ceiver operator characteristic (ROC) curves. Analyseswere performed using principles from the National Statistical Analysis
Committee for Clinical Laboratory Standards, NCCLSdocument GP10-T (ISBN 1-56238-213-6). The receiver The relationship between the dose of tacrolimus and operator curves were displayed using a logistic regres- the trough blood concentrations of tacrolimus was ana- sion model to calculate the predictive accuracy of this lyzed, using samples collected after 2 or more days of model. The model includes tacrolimus blood concen- tacrolimus administration. The relationship of tacro- trations as continuous data and occurrence of rejection, limus dose to steady-state tacrolimus trough levels was toxicity, or nephrotoxicity as the dependent variable.
assessed using a repeated-measure analysis of variance Bootstrapping and cross-validation methods were used model. The predictive relationship between tacro- to correct for the bias that results from using the same limus concentration (measured using the PRO-Trac™ II data for both fitting and testing the accuracy of the ELISA) and the subject’s risk of experiencing endpoint model. PC-SAS release 6.11 was used for all the statisti- events was evaluated using logistic regression and Cox proportional hazard regression analyses. Liver func- Data collection and management were performed tion tests were added to the model to assess their ability under the supervision of an independent contract re- search organization. Quality assurance procedures in- The logistic regression model underlying these anal- cluded monitoring of data to ensure that complete, timely, and accurate data were submitted and that pro-tocol requirements were followed.
The logit (probability of event) = α + β X, where α is the intercept parameter, and β is the vector ofslope parameters.
The pretransplant diagnosis and the demographics of For the nephrotoxicity, toxicity, death, and retrans- the study subjects are listed in Table I. In total, 111 sub- jects were enrolled at six sites. Ten percent of the sub-jects were hepatitis B positive, 35% of the subjects X = (maximum tacrolimus trough level).
were hepatitis C positive, 18% were diabetic, and 5% were on dialysis. A total of 91 subjects receivedtacrolimus treatment throughout the 12 weeks of study.
X = (minimum tacrolimus trough level, Twenty subjects received less than 12 weeks of treat- ment with tacrolimus, and the reasons for early termi-nation of treatment were death, retransplantation, tox- The Cox proportional hazard regression model was as icity resulting in conversion to cyclosporine, or Tacrolimus was administered intravenously during the immediate postoperative period at two sites. At onesite, IV doses of tacrolimus were administered on an where h (t) is an arbitrary and unspecified baseline as-needed basis to achieve desired blood levels of hazard function, z is the vector of measured explana- tacrolimus, followed by orally administered mainte- tory variables for the ith individual, and β is the vector nance doses. At the second site, the standard of care of unknown regression parameters associated with the called for tacrolimus to be administered intravenously at the time of surgery and for 2 to 3 days postopera- For the nephrotoxicity, toxicity, death, and retrans- tively, when patients often have difficulty tolerating orally administered drugs. After the immediate postop-erative period, maintenance therapy was provided as z = (maximum tacrolimus trough level).
oral doses. The mean oral tacrolimus dosage during week 1 was 0.07 mg/kg/day, was essentially stable at0.10 to 0.11 mg/kg/day during weeks 2 through 9, de- z = (minimum tacrolimus trough level, clined to 0.09 mg/kg/day during weeks 10 and 11, and was 0.07 mg/kg/day at week 12. Tacrolimus was ad- 544 · J Clin Pharmacol 2001;41:542-551
Table II Distribution of Clinical Endpoints
First Event
Clinical Endpoint
Events (n)
Only (n)
Figure 1. Relationship between tacrolimus dose (mg/kg/day) andsteady-state whole-blood trough concentrations of tacrolimus. ministered twice daily in all the subjects. Mean trough bution of the clinical endpoints reached is shown in blood concentrations of tacrolimus for the correspond- Table II. Any instance of rejection not confirmed by ing time periods were 10.4 ng/ml during week 1, histology was excluded from analysis. Forty-seven per- trending downward slightly to a low of 7.7 ng/ml dur- cent of the first-rejection episodes occurred within the ing week 11, and was 8.1 ng/ml during week 12. The re- first 10 days, 16% occurred between 11 and 20 days, lationship of dose to tacrolimus blood concentrations 13% occurred between 21 and 30 days, and 24% after for individual subjects is shown in Figure 1. The ability 30 days of transplantation. During the 12 weeks of this to predict the trough blood concentrations of tacro- study, patient survival was 97% (3 of 111 subjects limus based on the dose administered for a given indi- died), and graft survival was 93% (8 of the 111 subjects Clinical Endpoints
Logistic Regression Analysis
Of the 111 subjects enrolled in the study, 60 (54%) The clinical data were subjected to logistic regression experienced a total of 95 clinical endpoint events.
analysis to determine the relationship between blood Thirty-six subjects experienced acute rejection, 38 sub- concentrations of tacrolimus and clinical endpoints.
jects experienced nephrotoxicity, 10 subjects experi- The results are summarized in Table III.
enced other toxicity thought to be related to tacrolimus, Acute rejection. Based on the analysis of the 0- to 3 subjects died, and 8 were retransplanted. The distri- 7-day window prior to a biopsy-proven rejection event, Table III Summary of Logistic Regression Analysis
Number of
Odds Ratio
Acute rejection with significant mean LFT there is a statistically significant (p = 0.0465) relation-ship between increasing trough tacrolimus blood con-centrations and decreasing risk of acute rejection. Thisanalysis controls for the additive predictive effects ofmean liver function tests in the same time window byincluding them as covariates in the regression model.
The odds ratio associated with increasing tacrolimustrough concentrations and the risk of acute rejection is0.80 (mean liver function tests controlled).
Nephrotoxicity. Based on the analysis of the 0- to 7-day window prior to nephrotoxicity, a statisticallysignificant (p = 0.0001) correlation between increasingtacrolimus trough concentrations and increasing risk ofnephrotoxicity is demonstrated. The odds ratio associ- Figure 2. Plot of incidence rate for nephrotoxicity (circles), rejec- ated with increasing tacrolimus levels and the risk of tion (squares), and toxicity (triangles) using 0- to 7-day time window Toxicity. A statistically significant correlation (p = 0.0387) of increasing tacrolimus trough concentrationsand increasing risk of toxicity is found in the 0- to tacrolimus blood levels increase, and the probability 14-day window, with a supportive but nonstatistically of toxicity requiring a reduction in tacrolimus dosage significant correlation (p = 0.0964) in the 0- to 7-day increases modestly as tacrolimus concentrations window. The risk associated between increasing tacrolimus trough concentrations and toxicity (odds ra-tio of 1.071) is less pronounced than that for acute re- Cox Proportional Hazard
Regression Analysis
Relationship of Tacrolimus
The results with the Cox model as reported in Table IV Levels to Clinical Endpoints
were consistent with the results from the logistic re-gression analysis. The directional relationship of The probability of nephrotoxicity, rejection, and toxic- tacrolimus trough concentrations to the risk of acute re- ity based on logistic regression analysis is plotted in jection, nephrotoxicity, and toxicity is the same as Figure 2. This figure indicates that the probability of re- those of the logistic regression analysis. The magni- jection decreases as whole-blood levels of tacrolimus tudes of the risk ratios were similar to the odds ratios increase, the probability of nephrotoxicity increases as for the logistic regressions, although the risk ratio for 546 · J Clin Pharmacol 2001;41:542-551
MONITORING TACROLIMUS BLOOD CONCENTRATIONS Table IV Summary of Cox Proportional Hazards Analysis
Coefficient of
Risk Ratio
Acute rejection with significant mean LFT rejection and nephrotoxicity was less using the Coxanalysis. The strength of the relationship between in-creasing levels of maximum tacrolimus trough concen-trations and the risk of toxicity is greater in the Coxmodel.
Clinical Sensitivity and Specificity
Clinical accuracy of tacrolimus blood concentrationsin predicting the occurrence of primary clinical end-points is summarized graphically in the ROC curvespresented in Figures 3 through 6. Although thetacrolimus blood concentration has a statistically sig- Figure 3. Receiver operating characteristic curve for rejection with nificant contribution in the prediction of acute rejec- trough concentration in the 0- to 7-day window. This curve describes tion, ROC curves for rejection indicate that the liver that tacrolimus blood concentrations alone cannot differentiate be- function tests are the major contributors to differentiat- tween acute rejection and a nonevent with good sensitivity. ing the occurrence of acute rejection from a nonevent(Figures 3, 4). The optimal clinical sensitivity/specific-ity pairs for acute rejection, based on the maximumALT value in the 7-day window prior to the event, were88% and 75%, respectively, at 200 IU/L. Described interms of clinical sensitivity and 1-specificity, the ROCcurves for nephrotoxicity and toxicity (Figures 5, 6) in-dicate that tacrolimus blood levels as measured byPro-Trac™ II ELISA in the 0- to 7-day window are ableto differentiate the occurrence of these adverse eventsfrom nonevents.
For nephrotoxicity and toxicity, the trough concen- trations that give the highest clinical sensitivity/speci-ficity pairs are summarized in Table V. These clinicalstudy results would indicate that discrimination for Figure 4. Receiver operating characteristic curve for rejection with toxicity is greatest at trough concentrations of approxi- trough concentrations and liver function tests (max ALT) in the 0- to mately 12 ng/mL and that for nephrotoxicity, discrimi- 7-day window. This curve describes that liver function tests can pre- nation is greatest at a range from 12 to 15 ng/mL. Con- dict acute rejection with high sensitivity. Figure 5. Receiver operating characteristic curve for nephrotoxicity Figure 6. Receiver operating characteristic curve for toxicity with with trough level in the 0- to 7-day window. trough level in the 0- to 7-day window. This curve describes thattrough levels can differentiate adverse effect from a nonevent. centrations of 15 ng/mL, which demonstrate higher variation in the pharmacokinetics, and the need for positive predictive values and greater specificity, are long-term compliance to ensure graft survival in trans- supported by current standards of practice.
plant patients.8-11 The importance of the need for thera- There was no correlation between the trough blood peutic monitoring of tacrolimus is also supported by concentrations of tacrolimus and the time to first- the present study, confirming the poor correlation be- rejection episode or the time to nephrotoxicity or time tween the daily dose (mg/kg/day) and the steady-state whole-blood concentrations achieved.
During the early clinical trials, tacrolimus concen- DISCUSSION
trations were measured in plasma due to nonavailabil-ity of an assay to measure the concentrations in whole Therapeutic monitoring of tacrolimus is routinely per- blood. An analysis of tacrolimus concentrations in formed in transplant patients. Therapeutic monitoring these early studies indicated that nephrotoxicity, when of tacrolimus has been recommended due to the nar- other nephrotoxic factors were excluded, was associ- row therapeutic index, large inter- and intraindividual ated with high plasma trough concentrations.6 Elevated Table V Clinical Sensitivity and Specificity of Tacrolimus Trough Concentrations
for Nephrotoxicity and Toxicity Requiring Dose Reduction (in percentages) Predictive Values
Trough Concentration
548 · J Clin Pharmacol 2001;41:542-551
MONITORING TACROLIMUS BLOOD CONCENTRATIONS plasma tacrolimus concentrations and a higher rate of centration to the incidence of rejection in liver trans- renal dysfunction, often requiring dialysis, were ob- plant patients using the MEIA procedure19 contrasted served in liver transplant patients with poor graft func- to the observations in this study (Figure 2).
tion.24-25 This association was subsequently confirmed This study used logistic regression analysis and a in a single-center study.15 A plasma concentration– Cox proportional hazards regression model to evaluate guided regimen was developed that reduced the inci- the relationship between blood concentration and clin- dence of tacrolimus side effects while maintaining ade- ical endpoints within a 7-day window. This approach, quate immunosuppression.26 In contrast, a retrospec- applied to a 12-week posttransplant time period when tive analysis of 13,000 samples from 248 liver most endpoints occur and complete data collection can transplant patients suggested a poor correlation be- be made with reasonable confidence, has been shown tween plasma concentration and toxicity.27 to be successful in past analyses.19 These analyses do Subsequently, whole blood has become the pre- not predict an individual subject’s response to a spe- ferred matrix for tacrolimus concentration measure- cific tacrolimus concentration but instead provide the ment.11 In a study of kidney transplant patients, whole- clinician with an assessment of the relative risks of blood concentrations of tacrolimus correlated better acute rejection and nephrotoxicity associated with the with kidney function than plasma concentrations.14 A given tacrolimus blood concentration. This risk assess- similar association between blood concentration and ment, as shown here and by others,19 is suggested to be toxicity was reported in a retrospective analysis of mul- dependent on the monitoring methodology.
tiple clinical trials in renal transplant patients.19 The ROC curve analysis attempts to provide the cli- There have been conflicting reports regarding the as- nician with data that can be used in direct patient man- sociation of trough plasma or whole-blood tacrolimus agement. These curves suggest that ALT values may concentrations and acute rejection in liver transplant provide the best clinical sensitivity and specificity for patients. Whole-blood concentrations have been re- the prevention of acute rejection within a 7-day win- ported to correlate well,17,27 while whole-blood or dow. Optimal sensitivity/specificity pairs occur at ALT plasma concentrations showed poor correlation15,19 or concentrations of approximately 200 IU/L. Tacrolimus no significant difference between patients with and concentrations alone were not sufficient to discrimi- without rejection episodes.28-30 In pediatric liver trans- nate rejection from nonevents. This is perhaps related plant patients, rejection was shown to be most frequent to some of the variability in the immunosuppressive at blood concentrations less than 10 ng/mL.16 However, regimen used in the study patients. While all the pa- a more recent study did not show an association be- tients received tacrolimus as the primary immunosup- tween blood concentration and rejection in pediatric pressive agent, 88% of the patients also received methylprednisolone, 53% of the patients were also on Similarly conflicting associations between tacro- prednisone, and 44% of the patients were on myco- limus concentrations and acute rejection have been re- phenolate mofetil. Less than 5% of the patients re- ported for renal transplant patients.13-14 In a retrospec- ceived azathiporine or OKT3. It was not possible to tive analysis of trough whole-blood concentrations carry out statistical analysis of the subgroups due to within a 7-day window before the onset of rejection, limitations in the number of subjects in each group.
blood concentrations were well correlated with the on- In contrast, tacrolimus concentrations alone could set of rejection.19 As blood concentrations increased, discriminate between nephrotoxicity and nonevents the incidence of acute rejection was reduced while the with optimal sensitivity/specificity achieved at ap- incidence of adverse events was increased.
proximately 12 ng/mL. This information provides a A microparticulate enzyme immunoassay (MEIA) confirmation of the evolving clinical standard of prac- procedure for the IMx® analyzer20 and an ELISA proce- tice of reducing the upper limit of the recommended dure21,22 are the two commercially available immuno- trough tacrolimus blood concentrations from 20 ng/mL assays for the measurement of tacrolimus in whole as recommended by the Lake Louise Consensus re- blood. In this study, we validated the clinical utility of port.11 Even though not all potential nontacrolimus the ELISA methodology. This method correlates well causes of nephrotoxicity were assessed in this study, with the HPLC/MS/MS reference methodology by lin- none of the subjects exhibiting nephrotoxicity were re- ear regression, Bland/Altman analysis, and Student’s ceiving aminoglycosides or amphoterecin B during the t-test.21,22 Correlation of the ELISA to the MEIA method- 7-day window prior to the nephrotoxic event.
ology shows a statistically significant difference be- In conclusion, monitoring tacrolimus blood concen- tween the two assays.22 The inability to correlate con- trations by the PRO-Trac™ II ELISA method provides the clinician with information of predictive value for 14. Japanese FK 506 Study Group: Japanese study of FK 506 on kid-
managing the risk of nephrotoxicity and acute rejection ney transplantation: the benefit of monitoring the whole blood FK in liver transplant patients. Routine monitoring of 506 concentration. Transplant Proc 1991;23:3085-3088.
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Goldstein R, Husberg B, Gonwa TA, Klintmalm G: FK506 trough lev-
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DOSAGE FORMS AND STRENGTHS A long-term open-label extension study of subjects from the two short-term efficacy studies was also conducted 12.2 Pharmacodynamics in which subjects were treated with 3900 mg/day for up to 5 days during each menstrual period for up to Tranexamic acid, at in vitro concentrations of 25 - 100 M, reduces by 20 - 60% the maximal rate of plasmin lysis (tranexamic a

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Terms of Reference HEALTH SYSTEM MODERNIZATION PROJECT Consultant Terms of Reference 1. Background One of the components of the Albanian Health System Modernization Program is to make a thorough assessment of health technologies at public health care providers and an in-depth analysis of supportive systems and standards at the same in order to increase the effectiveness and eff

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