1. Objective: To utilize preclinical and phase I PK/PD data from a new quinolone (Q) and relevant public domain data to develop an exposure-response model for serum creatinine level increase by Q to support dose selection for subsequent clinical studies. Background: Reversible serum creatinine elevations were observed during development of a novel Q that may confound clinical safety monitoring. Glomerular filtration rate (GFR) remained constant while creatinine urinary clearance decreased suggesting the Q selectively inhibits creatinine renal tubular secretion. Methods: A population PK model was linked to a PD model of creatinine dynamics assuming competitive inhibition, consistent with preclinical data suggesting competitive inhibition of creatinine transport by Q. The PD model consisted of the following equation: d[Crn]/dt = ([Crn].GFR + RateCrnIn - RateCrnSec*[Crn])/VolCrn; where [Crn], GFR, RateCrnIn, RateCrnSec and VolCrn denote serum creatinine concentration (mg/dL), glomerular filtration rate (dL/Hour), zero order creatinine production rate (mg/Hour), creatinine tubular secretion rate (dL/Hour) and creatinine volume of distribution (dL). RateCrnSec was described as RateCrnSec = Vmax*[Crn]/(Km*(1 + [Q]/Ki) + [Crn])) where [Q] denotes the Q serum concentration. The resulting model was used to simulate Q dose dependent increase in serum creatinine. Creatinine dynamics parameters were derived from the literature. Results: Model supported competitive inhibition of serum creatinine secretion (Ki 156 ng/mL, ED50, 40 mg) by Q. Simulations showed that maximum serum creatinine increase occurred at Q doses of 200mg IV QD. Conclusion: Q may competitively inhibit serum creatinine secretion with near maximum increase at 200mg IV QD. Hence IV Q doses above 200mg will not produce major additional increases in serum creatinine level. ABSTRACT SUMMARY OF MAJOR FINDINGS SCHEMATIC OF GENERAL APPROACH METHODS Model Based Dose Selection of a Quinolone to Minimize Drug Induced Serum Creatinine Elevation S. Song 1, S. Rohatagi 1, P.K. Wickremasingha 1, T. Khariton 2, S. Kshirsagar 2, T.J. Carrothers 2, J. Kuwabara-Wagg 2 1 – Daiichi Sankyo Pharma Development, Edison, NJ; 2 – Pharsight Corporation, Mountain View, CA BACKGROUND Serum creatinine elevations occur in association with Q exposure Mean maximal elevation above baseline was approximately 35% Majority of elevation occurs within the first 24 hours of exposure In most cases, creatinine levels remain within the normal range This effect is not expected to be dose-limiting since ●Elevation appears to saturate at doses greater than 200 mg IV QD ●Elevations are completely reversible upon cessation of Q dosing and return to normal within 6 days of Q last dose Preclinical data suggest that serum creatinine elevation results from Q mediated, competitive inhibition of creatinine renal tubular secretion Simulations based on a physiological based model of human creatinine dynamics demonstrate that the proposed mechanism of elevation is consistent with the general time course of clinically observed creatinine elevations Q is a novel quinolone antibiotic in phase I development Serum creatinine elevations in response to Q administration were observed preclinically in rats, rabbits and monkeys Preclinical in-vitro studies demonstrate that: 14 C-creatinine is transported predominantly via hOCT2 (a human organic cation transporter), moderately, by hOCT2-A, and to a negligible extent by other organic cation transporters (hOCT1 & hOCT3) and organic anion transporters (hOAT1, hOAT2, hOAT3 & hOAT4) Q inhibits creatinine transport by hOCT2 and hOCT2-A transporters The kinetics of this inhibition are competitive Ki values for Q mediated inhibition of creatinine transport are estimated to be 1.8 and 0.7 μM for hOCT2 and hOCT2-A mediated transport, respectively Genetic variants of the hOCT2 and hOCT2-A genes associated with decreased transporter substrate affinity and/or increased turnover rates have been identified An early multiple dose phase I investigation of Q was stopped due to observed moderate elevations of serum creatinine (400 and 800 mg dose groups) Most subjects experienced such elevation with a mean elevation from baseline of 35% Comparable elevations were observed in an earlier single dose study (100 and 200 mg dose groups) Smaller elevations were also observed in lower dose groups (single dose study), e.g., 25 and 50 mg Serum creatinine elevations were also noted in at least two other phase I studies EXPLORATORY ANALYSIS To utilize preclinical and phase I PK/PD data for a new quinolone, Q, and relevant public domain data to develop a exposure-response model for serum creatinine elevation Exploit the model to establish whether the clinically observed time course and extent of serum creatinine elevation in response to Q administration is consistent with Q mediated competitive inhibition of creatinine renal tubular secretion The general approach consisted of the following steps: Exploratory data analysis of phase I data Utilize phase I PK data to develop a PK model for Q Implement an established, public-domain, creatinine turnover model Based on preclinical in-vitro and phase I data link the PK model to the creatinine turnover model Simulate the relationship between Q dosing regimen and serum creatinine elevation Compare the observed to the predicted serum creatinine elevations Left Panel: Median % change of serum creatinine from baseline as a function of day for Q treatment (upper curve) and placebo (lower curve) arms of a phase I renal function study. Note that 800 mg Q was administered via a 1-hour infusion on days 1, 2, 3 and 4. These days are denoted by the space between the solid vertical lines. Right Panel: Corresponding median % change of serum creatinine from placebo as a function of day for the phase I renal function study. OBJECTIVES Exploratory analysis of phase I renal function study data completed ●Mean and median serum creatinine percentage changes from baseline plotted as a function of time for both placebo and Q treatment arms ●Difference between the median % change in serum creatinine from baseline for the Q treatment group and the comparable change from baseline for the placebo group calculated and plotted as a function of time ●Concurrent changes in estimated Glomerular Filtration Rate (GFR) and Creatinine Urinary Clearance before, during and after Q dosing, plotted as a function of time. Pooled phase I study data then used to calculate and plot the median % change from baseline of serum creatinine as a function of dose and an Emax function of dose fitted to the data An established model of creatinine dynamics implemented (PD model) ●Parameter values obtained from the literature Phase I PK data used to developed a PK Model for Q The PK and PD models were linked under the assumption of Q mediated competitive inhibition of creatinine renal tubular secretion Linked PK/PD model then used to simulate the time course of serum creatinine elevation as a function of Q dosing regimen Simulated and observed serum creatinine profiles qualitatively compared Serum Creatinine Elevations at 800 mg QD average about 30% above baseline CREATININE SIMULATION RESULTS Q effects on renal creatinine clearance were characterized in a phase I renal function study The objective was to assess whether Q-mediated serum creatinine elevation reflect Q- mediated decreases of glomerular filtration rate (GFR) and/or renal tubular creatinine secretion 800 mg Q was administered daily for 4-days as an I.V. infusion Creatinine clearance was calculated using a 24-hour urine specimen and estimated two days prior to dosing, on the last day of dosing, and, 1-week after the final dose Glomerular Filtration Rate (GFR) was measured using the cold iohexol “gold standard” two days prior to dosing, on the last day of dosing, and, 1-week after the final dose Physiologically, urinary creatinine clearance consists of two components, one reflecting glomerular filtration (GFR) and another reflecting renal tubular secretion. This is because renal tubular creatinine reabsorption is negligible. RESULTS: Q RENAL EFFECT Since creatinine clearance is given by the sum of GFR and renal tubular secretion, and, Q has minimal effects on GFR, the effects of Q on creatinine clearance are inferred to be mediated by reduced renal tubular secretion of creatinine. Q renal effect is predominantly at the level of creatinine tubular secretion The serum creatinine elevation effect is near maximum at 200 mg QD RENAL FUNCTION STUDY Simulated serum creatinine profiles as a function of regimen are comparable to those observed in phase I studies CREATININE DYNAMICS MODEL Simulated serum creatinine as a function of time for administration of 50, 100, 400 and 800 mg QD IV for 14-days. Simulations were based on a physiological model of serum creatinine dynamics in which Q mediates a competitive inhibition of creatinine renal tubular secretion. Simulated percentage change from baseline of serum creatinine as a function of time for adminstration of 400 and 800 mg IV Q for 14 days. Filled triangle and squares denote the observed median % changes of serum creatinine from placebo for the 400 and 800 mg treatment arms of a phase I study. PK MODEL SUMMARY AND PK/PD LINK Based on preclinical data, Q is assumed to act as a competitive inhibitor of renal tubular secretion such that RateCrnSec is a function of plasma Q levels, [Q]. Plasma (central) Q levels were described using a 2-compartment PK model Linked PK/PD model equations were solved for dosing regimens of interest to simulate: Plasma Q levels as a function of time Serum creatinine levels as a function of time