A randomized concentration-controlled clinical trial (RCCCT) is an alternate experimental design to the standard dose-controlled study. In a RCCCT, patients are randomly assigned to predefined plasma or blood drug concentration ranges (low, medium, and high). With the caveat that concentration ranges are sufficiently separated, this design should enhance the ability to discover important concentration response relationships. FK-506, a potent and promising immunosuppressive agent for prevention and treatment of graft rejection, has shown significant clinical activity in some immune-mediated disorders. To implement the RCCCT design, a novel FK-506 intelligent dosing system (IDS) was used to guide all doses to prospectively achieve the target concentration range specified in the study protocol. Patients enrolled in these trials suffered from a variety of autoimmune disorders, including multiple sclerosis, primary biliary cirrhosis, psoriasis, autoimmune chronic active hepatitis, and nephrotic syndrome. We observed excellent predictive performance of the IDS for all patients. The accuracy (mean prediction error) of the IDS was −0.022 ng/ml and the precision (standard deviation of the prediction error) was 0.119 ng/ml. Thus, the IDS is both accurate and reproducible for autoimmune patients. We conclude that the RCCCT design, guided by an accurate and precise IDS, is an informative and cost-effective approach for evaluation of efficacy and safety of effective but highly toxic agents. © 1993 Raven Press, Ltd., New York

Doyle, H

Fung, J

Lieberman, R

McCauley, J

McMichael, J

Starzl, TE

Thomson, A

Van Thiel, D

English

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Computer-guided concentration-controlled trials in autoimmune disorders

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Computer-Guided Concentration-Controlled Trials in Autoimmune Disorders

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Tht!rapt!u//c aru~ Morr;rorirr!f tS:51(}"'513 Q 1993 Raven Press. Ltd .. ~ew York Computer-Guided Concentration-Controlled Trials in Autoimmune Disorders *J. McMichael. *+R. Lieberman, *H. Doyle, *J. McCauley, :J:D. Van Thiel, *A. Thomson, *J. Fung, and *T. E. Starzl *Transplantation Institute. University of Pittsburgh. Pittsburgh. Pennsylvania; tStaff College. Center for Drug Evaluation and Research. Food and Drug Administration. Rockville. Maryland; and Oklahoma Transplant Institute. Oklahoma City. Oklahoma. U.S.A. Summary: A randomized concentration-controlled clinical trial (RCCCT) is an alternate experimental design to the standard dose-controlled study. In a RCCCT. patients are randomly assigned to predefined plasma or blood drug concentrauon ranges !low. medium. and high). With the caveat that concen-tration ranges are sufficiently separated. this design should enhance the ability to discover important concentration response relationships. FK-506. a potent and promising immunosuppressive agent for prevention and treatment of graft rejection. has shown significant clinical activity in some immune-mediated disorders. To implement the RCCCT design. a novel FK-506 intelligent dosing system (IDS) was used to guide all doses to prospectively achieve the target concentration range specified in the study protocol. Patients enrolled in these trials suffered from a variety of autoimmune disorders. including mUltiple scle-rosis. primary biliary cirrhosis. psoriasis. autoimmune chronic active hepatitis. and nephrotic syndrome. We observed excellent predictive performance of the IDS for all patients. The accuracy (mean prediction error) of the IDS was - 0.022 ng:ml and the precision (standard deviation of the prediction error) was 0.119 ng/m1. Thus. the IDS is both accurate and reproducible for autoimmune patients. We conclude that the RCCCT design. guided by an accurate and precise IDS. is an informative and cost-effective approach for evaluation of efficacy and safety of effective but highly toxic agents. Key Words: Concen-tration-controlled artiticial intelligence-Dynamic dosing-Autoimmune dis-eases. I n late 1991. we began randomized concentration-controlled clinical trials (RCCCTs) designed to evaluate the efficacy and toxicity of FK-506 in cer-tain autoimmune diseases being studied at the Uni-versity of Pittsburgh Medical Center (UPMC) (Ta-ble I). Concentration-controlled trials (CCTs) were wnsidered the best choice tor evaluating FK-506 because of the narrow therapeutic index of FK-506 Address ..:orrespondence and repnnt requests to Mr. John \1cMi..:haet at University of Pittsburgh. 3601 Fifth Avenue. 5C Falk Clinic. Pittsburgh. PA lS:!\3. l.S.A. 510 as well as the considerable sample size advantages that CCTs offer over standard trial designs (I). Sub-stantially smaller sample sizes can be used when conducting CCTs since CCTs. by design. minimize interindividual drug level variability within compar-ison groups and. consequently. decrease within-group clinical variability. This design will facilitate early assessment of efficacy. while prOViding infor-mation on concentration (dose) response. Another reason we found CCTs very attractive was that this pilot trial design does not necessitate a placebo group. which we believed would be unethical for many of the diseases we wished to study. CONCENTRATION TRIALS IN AUTOIMMUNE DISEASES 511 TABLE 1. Autoimmune diseases Rheumatology Systemic sclerosis Polymyositis dermatomyositis Rheumatoid arthritis Systemic lupus Systemic vasculitides 8eh<;et's disease Ophthalmology Uveitis Episcleritis Retinitis Gastroenterology Autoimmune chronic active hepatitis Inflammatory bowel disease Primary biliary cirrhosis Primary sclerosing cholangitis Sprue Neurology Multiple sclerosis Chronic inflammatory demyelinating polyneuropathy Autoimmune inner ear disease Endocrinology Type I diabetes mellitus Nephrology Nephrotic syndrome Glomerulonephritis Dermatology Alopecia areata totalis and universalis Pyoderma gangrenosum Severe psoriasis Epidermolysis bullosa METHODS Approximately 300 patients meeting the specific entry criteria for the protocol in which they were enrolled were randomized to either a high. medium. or low FK-506 plasma concentration range using a block randomization design for three groups. This allocation design ensures that an equal number of ratients will be in anyone of the treatment groups at any point in time. Randomization was carried out hy sequential draw of assignment. and the three block sizes used were selected randomly with equal rrobability. The order of assignment within a block was determined by generating a random number be-tween 0 and I and then rearranging the random numbers in ascending order. for these studies. the low average plasma concentration of FK-506 was targeted at O.:! ng/ml. with a range from 0.1 to 0.4 ng/ml. The intermediate average concentration was targeted at ll.6 nglml. with a range from OA 10 ll.H. and the high average plasma concentration target was 1.0 nglml. with a range from lUI to 1.2 ng/ml. This approach substitutes for a preconceived mgi kg/day dosing scheme. which may he completelv inappropriate for a given patIent (Fig. I), The start-ing oral dose regImen of FK-506 was usually 0.075 mg/kg/day in divided doses given every 12 h. In the interest of patient safety and compliance. all pa-tients enrolled in these studies were prerandom-ized. kept in the low FK-506 plasma concentration range of 0.1-0.4 ng/ml until they were stable. and then moved to the zone to which they had been randomized. Failure of a patient to achieve or be maintained within his/her randomized zone was considered a treatment failure. To determine the FK-506 dosage required to achieve the desired tar-get plasma concentration. an artificial intelligence dosing system (IDS). which would predict drug dos-ages and concentrations. was developed. To use this dosing system. the physician enters the pa-tient's current FK-506 dose (mg/day). the patient's current plasma concentration (ng/mD. and the target plasma concentration (ng/mll. The IDS then calcu-lates the FK-506 dose required to achieve target concentration. In a CCT. patients are assigned to predetermined average plasma drug concentration ranges using an individualized dosing scheme. Simple linear regres-sion is used to test the null hypothesis that the mean change in efficacy and toxicity parameters (for con-tinuous variables) is not linearly related to FK-506 target plasma concentration. The XC test of associ-ation was used to test whether there is an associa-tion between the rate of nephrotoxicity at pre-defined time points and FK-506 plasma concentra-tion. Criteria for reducing a patient's FK-506 blood plasma concentration range included increase in the creatinine concentration of 150% above baseline. reduction in the creatinine clearance to <40 cc/min. \cvere neurotoxicity (as detined by tremors. sleep disturbances and seizures I. and development of new onset insulin-dependent diabetes. It was left to the discretion of the treating physi-6 E5 0> ~4 §3 <t ;::2 z ~1 z 80 o 5 10 15 20 25 30 DOSE mglday FIG. 1. :\ulOimmune ,bease pallents: starting dose versus con-(entrJlllln. The starling dailv dllse ot FK-506 !lIven appears 10 be unrelated tll the resultlngl:llncentrallon. fff~r 0"'1( M"nll. \,,1. 15 .. 'Va. 6. I99J 512 1. MCMICHAEL ET AL. cian whether a patient should remain in his/her ran-domized zone. should that concentration of FK-S06 not appear to be influencing the patient's disease state. If this occurred. the patient would be moved to the next zone and treated: however. he/she would be recorded as a treatment failure at the orig-inal zone to which he/she was randomized (intent to treat analysis). FK-S06 concentration in plasma was measured by enzyme-linked immunoabsorbent assay (ELISA), using a monoclonal antibody as previ-ously described (2,3). The coefficient of variation of this assay was 17% at 1.4 ng/ml, 14.4% at 2.9 ng/ml. and 12% at 5.7 ng/ml. The effective therapeutic range for FK-S06 was estimated to be 0.S-2.0 ng/ml in transplant patients. and is currently still being defined in patients with autoimmune disorders. The UPMC currently measures FK-S06 in both plasma and whole blood. and predictive models have been developed for both matrices. Fujisawa is still deter-mining which matrix is best for monitoring FK-S06. (Fujisawa Corporation. Deerfield. IL. unpublished data). RESULTS To validate our IDS. a prospective study was conducted at UPMC (4). Our patient population consisted of 32 adult liver (n = 17) and kidney (n = IS) transplant patients. Predictions of patient plasma concentrations were made throughout their clinical courses. Performance of the IDS was as-sessed using a standard prediction analysis. The mean prediction error( MPE). which is calculated as the mean difference between the observed and the predicted target values. was calculated to be 0.016 ng/ml. The root mean squared prediction error (RMSPE). which is calculated as the standard de-viation of the prediction errors. was 0.189 ng/ml. The 95% confidence interval (Cll for the mean pre-diction error was calculated to be between - 0.084 and 0.052. This brackets our calculated accuracy (including zero), indicating there is little or no bias in the system's dosing predictions. In 50- predictions of concentrations made in the autoimmune disease patient group. the M PE was calculated to be - lI.022 nglml. the RMSPE was cal-culated to be 0.119 nglml. and the 95%- CI was cal-culated to be between 0.011 and - 0.055 (Fig. 2). These results. as tabulated in Table 2. demonstrate the accuracv and preCIsion of this IDS and the util-r"~I a"I~ Monll. ror /5. So. o. IW.I (j) 2 z o ~ 1.6 II: ~ 1.2 () z gO.8 -Cl ~MK4 . () is ~ ° a.. ° 0.5 1 1.5 2 OBSERVED CONCENTRATIONS FIG. 2. Autoimmune disease patients: observed versus pre-dicted FK-506 concentrations. The close correlation between the observed and predicted concentrations using the IDS, ity of the system to move a patient to a desired concentration level and maintain that level. DISCUSSION The use of CCTs has been very effective in our early pilot studies to assess the efficacy and safety of FK-S06 in autoimmune disorders. Using this study design, our final analysis will provide infor-mation about the toxic properties of FK-506 as it relates to plasma concentration. We will also have a relatively rapid. clear picture of the efficacy of FK-506 in each of the autoimmune diseases studied and whether there is a relationship to plasma concentra-tion. The use of the IDS has been very effective in providing physicians a simple method by which study patients can be taken to a desired plasma con-centration and held there. This will simplify our analysis by providing clearly defined groups of stud v patients where statistical significance can be asce~tained for any of the parameters being exam-ined. Because using this IDS does not require any previous computer experience and i~ is user friendlv. it will help minimize the learmng curve associ~ted with dosing new agents. e.g., FK-506. with its large pharmacokinetic variability and nar-row therapeutic index. The IDS is ideally suited for multicenter trials since it would standardize therapy and aid in producing reliable homogenous results. independent of the study site. TABLE 2. ,J.utoimmuf/t' cii.I'l'lISt' rliflentJ' ;one statistics \-tean Zone .:oncentrallon SD :"IJo. Low n.27 n.l:! 10 \-tedium 0.66 0.16 10 High I.O!! n.19 10 CONCENTRATION TRIALS IN AUTOIMMUNE DISEASES 513 REFERENCES 1. Sanathanan LP. Peck CC. Temple R. Lieberman R. Pledger G. Randomization. PK-controlled dosing and titration: An integrated approach for designing clinical trials. Drug infor-mation Assoc J 1991 :25:425-31. 2. Venkararamanan R. Jain A. Warty V, et aI. Pharmacokinet-ics of FK506 in transplant patients. Trans Proc 1991 :23: 2736-40. 3. Jain A. Abu-Elmagd K. Abdallah H, et aI. Pharmacokinetics of FK506 in liver transplant recipients following continuous intravenous infusion. J Clin Pharm (in press). 4. McMichael J. Irish W. McCauley J, et aI. Evaluation of a novel "Intelligent" dosing system for optimizing FK506 therapy. Trans Proc 1991:23:2780-2. Tlrrr Dr,,'l MOil", Vol. 15. No.6. I99J 

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Computer-guided concentration-controlled trials in autoimmune disorders

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