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Pharmacokinetic Modeling and Simulation of the Interaction between Moxifloxacin and RifapentineMarjorie Imperial, Kelly Dooley and Rada Savic
10/28/16
1
• Shorten the standard 6 month regimen• Improve patient adherence
• Prevent emergence of drug resistance
2
Proposed strategy: Moxifloxacin and rifamycins• Murine models suggest that moxifloxacin and
rifamycin combination therapies may improve cure rates Rifaquin Zvada AAC 2012 56: 4471
Dorman 2015 Am J Respir Crit Care Med. 1;191(3):333-43
10/28/16
Moxifloxacin and rifamycins for tuberculosis treatment
310/28/16
Efficacy concern: Induction of phase II drug metabolizing enzymes
Safety concern: Prolongation of QT interval by moxifloxacin
Time
Mox
iflox
acin
(ug/
mL)
Sulfa
te C
ongu
gate
(ug/
mL)
Time
Moxifloxacin Conc (ug/mL)∆∆𝑄𝑇𝑐𝐹(𝑚𝑠𝑒𝑐)
Weiner 2007 AAC 51(8):2861-6Darpo 2015 CPT 97(4):326-35
How do high doses of rifapentine affect moxifloxacin efficacy and toxicity?
4
Decreases in exposure of moxifloxacin has been observed when administered with rifapentine.
10/28/16
Works for safety, but how about efficacy?
Goal: Quantify the relationship between moxifloxacin and rifapentine drug-drug interaction
10/28/16 5
• John Hopkins Hospital in Maryland
• 15 healthy volunteers recruited • 24-64 years • 9 African American, 4
Caucasian, 1 Hispanic, and 1 Asian
continental breakfast (750 kcal, 20% fat). Other medications, alcohol, and smok-ing were not permitted.
(ii) Safety monitoring. On days 3, 9, 12, 15, 18, and 33, subjects underwent adirected review of systems to identify adverse events. A comprehensive metabolicpanel was performed and a complete blood count taken on the subjects on days3, 12, and 18. Signs and symptoms were graded according to the National CancerInstitute Common Toxicity Criteria, version 2.0 (http://ctep.cancer.gov/forms/CTCv20_4-30-992.pdf).
Drug concentration analysis. (i) Determination of plasma concentrations ofMXF. Plasma concentrations of MXF were determined using a validated high-performance liquid chromatography (HPLC) assay. Samples were measuredusing a system consisting of a ThermoFinnegan P4000 HPLC pump (San Jose,CA) with an AS3000 fixed-volume autosampler, McPherson model FL-750 flu-orescence detector, Gateway E series computer (Poway, CA), and ChromQuestHPLC data management system. The plasma standard curve ranged from 0.20 to15 !g/ml. The lower limit of quantification was 0.02 !g/ml. Absolute recovery ofMXF from plasma was 90%. Within-sample precision (percent coefficient ofvariation) was 6.33%, and overall validation precision across all standards was1.59 (10 standard) to 5.13% (5 standard). All assays used an internal standard,difloxacin. No interferences were observed with 90 commonly used medications.
(ii) Determination of plasma concentrations of RPT and its metabolite 25-desacetyl-RPT. Plasma concentrations of RPT and 25-desacetyl-RPT were de-termined using a validated HPLC assay. Samples were measured using a systemconsisting of a ThermoFinnegan P4000 HPLC pump with an AS3000 fixed-volume autosampler, model UV2000 UV detector, Gateway E series computer,and ChromQuest data management system. The plasma standard curve rangedfrom 0.50 to 50 !g/ml. The lower limit of quantification was 0.10 !g/ml. Theabsolute recovery of RPT and 25-desacetyl-RPT from plasma was 95%. Within-sample precision was 3.61%, and overall validation precision across all standardswas 3.49% (50 standard) to 10.65% (0.50 standard) for RPT; those of themetabolite were similar. All assays used an internal standard, trimipramine. Nointerferences were observed with 90 medications.
PK and statistical evaluation. (i) Sample size. It was estimated that a samplesize of 10 subjects would achieve 80% power to test whether or not coadminis-tration of RPT resulted in an MXF area under the concentration-time curve(AUC) that differed from that observed with MXF alone by !10%, assuming anMXF AUC standard deviation of 5.4 !g · h/ml (twice that observed in previousstudies of healthy volunteers) and a significance level of 0.05 using a two-sidedone-sample t test (Avelox package insert). It was estimated that 11 subjectswould be needed to determine bioequivalence with 80% power at a 3% one-sided significance level using two one-sided tests if the treatment mean was 90%of the reference mean, with equivalence defined as 80% to 125% of the referencemean (30). Fifteen subjects were enrolled to ensure that there would be 11evaluable subjects.
(ii) PK parameters and statistical evaluation. PK parameters, including themean AUC, maximum plasma concentration (Cmax), time to maximum plasmaconcentration (Tmax), half-life (t1/2), clearance as a function of bioavailability
(CL/F), and volume of distribution (V/F) were calculated using noncompartmen-tal methods with WinNonlin software, version 4.1 (Pharsight, Cary, NC). Com-parisons involving AUC were restricted to a common exposure time for allpatients of 24 (MXF) or 48 (RPT and desacetyl-RPT) hours. Descriptive andstatistical analyses were performed using Intercooled Stata 9.0 software (Stata-Corp LP, College Station, TX). The calculated geometric mean ratio (GMR) anda 90% confidence interval (CI) were used to compare the Cmax, Tmax, AUC from0 to 24 h (AUC0-24), and t1/2 values of MXF alone and in the presence of RPT.P values using two-sided, one-sample t tests with an " of 0.05 are reported. Toestimate the effect of RPT on its own metabolism, similar procedures wereperformed using the PK parameters for RPT on study days 5 and 19.
RESULTS
Subjects. Fifteen subjects, including nine African Ameri-cans, four Caucasians, one Hispanic, and one Asian, wereenrolled; 3 were female and 12 were male. One subject with-drew for personal reasons after receiving two doses of MXF.Another withdrew after the first PK analysis, citing grade 1 sideeffects and job obligations. Thirteen subjects completed thestudy, three of whom were women. The mean age was 43.2years (range, 24 to 64 years). The mean dose was 5.27 mg/kgfor MXF and 11.9 mg/kg for RPT.
PK interaction between MXF and RPT. Figure 2 showsmean MXF plasma concentration-time curves after four dosesof MXF dosed at 400 mg once daily and after 15 days of 400 mgMXF once daily plus 900 mg RPT thrice weekly. The meanMXF AUC0–24 was 41.9 !g · h/ml for MXF alone and 34.4 !g ·h/ml for MXF coadministered with RPT (P # 0.0006) (Table1). The AUCday 19/AUCday 4 GMR was 0.83 (90% CI, 0.77 to0.89). The MXF t1/2 was 11.1 h on day 4 versus 8.9 h on day 19(P # 0.0033), and CL/F increased from 7.89 liters/h to 10.1liters/h (P # 0.0003). The Cmaxs and Tmaxs on days 4 and 19were not significantly different.
Autoinduction of metabolism by RPT. Figure 3 shows meanRPT and 25-desacetyl-RPT plasma concentration-time curvesafter one dose of RPT and after seven doses of 900 mg RPTthrice weekly. After one dose (day 5), the mean RPT AUC0–48
and t1/2 were 512.9 !g · h/ml and 18.5 h, respectively, and afterseven doses (day 19), these values were 410.2 !g · h/ml and
FIG. 1. Schematic of the dosing regimen and pharmacokinetic sample collection.
4038 DOOLEY ET AL. ANTIMICROB. AGENTS CHEMOTHER.
10/28/16 6
Study Details
Pharmacokinetic Data
Dose Simulations
Drug Drug Interaction Model
Healthy volunteers 336 observations Moxifloxacin
400 mg QD Rifapentine
900 mg 3x/weekly
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Modeling and Simulation
AbsorptionCompartment
CentralCompartment
MoxifloxacinDose
Transit𝑘-.,0123
𝑘4,0123
𝐶𝐿0123 𝑉0123⁄ ∗ (1 + 𝐸𝐹𝐹=>?→0123)
AbsorptionCompartment
CentralCompartment
RifapentineDose
Transit𝑘-.,=>?
𝑘4,=>?
𝐶𝐿=>? 𝑉=>? ∗ 𝐸𝑁𝑍⁄
Enzyme
𝑘CDE(1 + 𝐸𝐹𝐹=>?→=>?)
𝑘CDE
DrugDrugInteractionModel
10/28/16 8
Pharmacokinetic Data
Dose Simulations
Drug Drug Interaction Model
Healthy volunteers Moxifloxacin
400 mg QD Rifapentine
900 mg 3x/weekly
MoxifloxacinQD
RifapentineQD
400 mg 0 mg
600mg 600mg
800mg 1200mg
10/28/16 9
Modeling and Simulation
%𝐼𝑛𝑐𝑟𝑒𝑎𝑠𝑒𝑖𝑛𝐶𝐿0123 = 𝐸𝑀𝐴𝑋 ∗ 𝐶=>?
P
𝐸𝐶50P + 𝐶=>?P
ParameterEstimate(RSE)
EMAX(%) 52.5(35)
EC50(ug/mL) 12.0(37)
Gamma 5(FIXED)
10/28/16 10
Question: How will increases in moxifloxacin clearance affect drug efficacy?
Rifapentine Increased Moxifloxacin Clearance
c
• Pharmacodynamic drug-exposure target • In vitro, murine studies, and clinical trialsb
𝑓𝐴𝑈𝐶 𝑀𝐼𝐶⁄ ≥ 100• In vitro hollow-fiber PD infection modela
𝑓𝐴𝑈𝐶 𝑀𝐼𝐶⁄ ≥ 53• MIC
aGumbo 2004 J Infect Dis. 1;190(9):1642-51bSchentag 2003 Ann Pharmacother. 37:1287-1298, 1478-1488cRodriquez 2002 Int J Antimicro Agents. 20(6):464-7
10/28/16 11
Moxifloxacin Efficacy Target: fAUC/MIC
Rifapentine Dose affects Moxifloxacin Efficacy
12
MoxifloxacinDose 400mgQD 600mgQD 800mgQD
RifapentineDoseProportionofpatients withfAUC/MICratiobelowthe
requiredefficacyminimum0mg 19% 2% <1%
600mgQD 37% 10% 2%
1200mgQD 49% 16% 4%
Increased doses of moxifloxacin can compensate lost efficacy due to co-administration with rifapentine.
10/28/16
10/28/16 13
Can DDI Counteract Moxifloxacin Toxicity?
10/28/16 14
Can DDI Counteract Moxifloxacin Toxicity? ∆∆𝑄𝑇𝑐𝐹 based on Cmax
Summary
• Co-administation of rifapentine with current 400 mg moxifloxacin dose significantly increased proportion of subjects below fAUC/MIC efficacy threshold.
• Lost in efficacy was compensated with increased moxifloxacin dose.
• Drug-drug interactions may counteract moxifloxacin toxicity concerns at higher doses.
• Moxifloxacin 600 mg QD with rifapentine 1200 mg QD has similar efficacy and toxicity with moxifloxacin 400 mg QD.
10/28/16 15
Limitations/Future Directions
• PK data were from healthy volunteers, model needs validation with patient population
• RioMar- moxifloxacin and rifapentine QD
• Drug efficacy targets are not fully defined.
10/28/16 16
Acknowledgements
• Rada Savic• KellyDooley• Jenn Himba
• Savic Lab
10/28/16 17
18
Moxifloxacin Model fit
10/28/16 19
Population predictions
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Additional goodness of fit plots (Run 170)
Parameter Estimates %RSECL/F(L/h) 10.42 5Vc/F(L) 157.2 6MTT (h) 0.7016 24No.transitcompartments 4.161 65EMAX (%) 52.5 35EC50(ug/mL) 12.0 37𝛾 5 (FIXED)
Interindividual Variability(%CV)CL 14 10Vc 12 10MTT 76 32
ResidualStandardDeviationAdditive 0.072 12Proportional 0.28 10
RPTModelfit
10/28/16 20
Parameter Estimates %RSECL/F(L/h) 1.37 9Vc/F(L) 41.0 7MTT(h) 1.89 7No.transitcompartments 5.00 75Turnover halflife (h) 358 115EC50(mg/L) 2.27 34Emax 1(FIX)𝛾 10(FIX)
Interindividual Variability(%CV)CL 33 36Vc 25 30MTT 26 59Turnover halflife 152 78CovarianceforCL-V 76 38
ResidualStandardDeviationAdditive (mg/L) 0.90 12Proportional 0.12 9
Population predictions
Obs
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Basic goodness−of−fit plots (Run 72)
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Additional goodness of fit plots (Run 72)
10/28/16 21
0.0
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MOX
I con
c (u
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L)
, 400 mg MOXI daily
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10/28/16 22
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I con
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10/28/16 23
0.0
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MOX
I con
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10/28/16 24
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MOX
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RPT 1200 mg
AbsorptionCompartment
CentralCompartment
MoxifloxacinDose
Transit𝑘-.,0123
𝑘4,0123
𝐶𝐿0123 𝑉0123⁄ ∗ (1 + 𝐸𝐹𝐹=>?→0123)
AbsorptionCompartment
CentralCompartment
RifapentineDose
Transit𝑘-.,=>?
𝑘4,=>?
𝐶𝐿=>? 𝑉=>? ∗ 𝐸𝑁𝑍⁄
Enzyme
𝑘CDE(1 + 𝐸𝐹𝐹=>?→=>?)
𝑘CDE
DrugDrugInteractionModel
10/28/16 25
![DS MXF 614130 [E-mail]33](https://img.pdfslide.us/doc/110x75/615bde1d49937e585c75f1d4/ds-mxf-614130-e-mail33.jpg)
