Three significant covariate relationships were identified whereby metabolite clearance (CLoc), metabolite volume of distribution (Voc), and parent clearance (CLop) all increase linearly with increasing CRCL as shown in Figure 1. As such, these covariates were accounted for in the final model using Equation II. Inclusion of CRCL on CLoc explained 41% of the inter-individual variability (IIV) in CLoc, while CRCL on Voc explained 17% of the IIV, and CRCL on Clo pexplained only 4% in the IIV (but was kept in the final model as it was statistically significant).

Figure 4 shows goodness-of-fit plots of the base and final models for OC concentrations. As shown, in the base model, a bias is seen in the Concentration vs. population prediction (PRED) plot whereby concentration data of renally impaired subjects are systematically lying above the line of additivity (red dashed line), whereas the corresponding concordance plot of the final model shows no such bias. Parameter estimates of the final model are shown in Table II. All parameters were estimated with good precision as shown by the low relative standard errors. In general, the residual variability in the OP PK data was higher than that of the OC as indicated by the larger estimate of proportional residual error (σ prop) in Table II (0.4 as opposed to 0.17).

The visual predictive checks (VPCs) for OP and OC, stratified by renal function, show the simulated median and 95th and 5th percentiles (shaded region) and overlay of the observed data (Figures 4 and 5 respectively). Most of the observed data (open circles) lie within the shaded area (green) and there is no systematic bias around the simulated median (blue line). The exception is the VPC of OC in subjects with moderate renal impairment . The figure shows a slight bias with the model slightly under-predicting the observed exposures, however with majority of observed data points lying in the interval (green shaded area). Median simulated exposures (5th and 95th percentiles) of OC Cmin, Cmax, and AUC0-48hrs of various influenza treatment regimens for patients with mild, moderate or severe renal impairment are provided in Table III . Box plots are shown summarizing the distribution of OC Cmax and Cmin to visually compare various treatment regimens in subjects with moderate and severe renal impairment to regimens in subjects with normal renal function (Figure 7) . Simulations in Table III and Figure 7 indicate that in the severe renally impaired group (CRCL 10-30 mL/min), the current 75 mg qd regimen results in simulated OC exposures of Cmin, Cmax and AUC0-48hrs that are just under the 450 mg bid regimen but above the 150 mg bid regimen in normal subjects. The 30 mg qd regimen produced a Cmax and AUC0-48hrs which fell below that of the 150 mg bid regimens in patients with normal renal function, and an OC Cmin and AUC0-48hrs which exceed that of the 75 mg bid in normal subjects. Likewise for moderate renal impairment (CRCL 30-60 mL/min) a 30 mg bid satisfies the same dose selection criteria, whereas the current recommended dose of 75 mg bid produces exposures that exceed those of the 150 mg bid in subjects with normal renal function (Table III). In patients with mild renal impairment (CRCL 60-90 mL/min), the currently recommended 75 mg bid regimen produces the OC Cmin,Cmax and AUC0-48hrs that lie between the 75 mg and 150 mg bid regimens and hence satisfies the current dose selection criteria used (Table III). Table IV shows the simulated prophylaxis regimens for subjects with mild, moderate and severe renal impairment. A shown in the table, the newly recommended regimens of 30 mg qd and qod for moderate and severe impairment respectively provide Cmax, Cmin and AUC0-48hrs exposures that are more similar to the prophylaxis regimen of 75 mg qd in subjects with normal renal function when compared to the current regimens of 75 qd and qod.

Identification of New Oral Dosing Regimens for the Neuraminidase Inhibitor Oseltamivir (Tamiflu®) in Patients with Moderate and Severe Renal Impairment

Supported by Population Pharmacokinetics

METHODS

INTRODUCTION

OBJECTIVE

Mohamed A Kamal* (1), Barbera Brennan (1), Vishak Subramoney (1), Peter A Morcos (1), Nicolas Frey (2), Craig Rayner (1)

(1) Roche, Nutley, NJ, USA; (2) Roche, Basel, Switzerland 

RESULTS

CONCLUSIONS

Patients with renal dysfunction are more susceptible to influenza virus, and are at increased risk of complications from influenza1 . Chronic renal failure or severe renal impairment, marked by uremia and a creatinine clearance (CRCL) of 10-30 ml/min, is frequently encountered in the general population. In the US adult population, the prevalence of chronic kidney disease is estimated to be 11%. Renal insufficiency (CRCL 30-60 ml/min), or moderate impairment, is the intermediate stage at which symptoms of hypertension and anemia become present, but, unlike chronic renal failure, may reverse or stabilize with appropriate treatment. Mild renal impairment, also known as decreased renal reserve, is marked by a CRCL of 60-90 ml/min. Many patients in this renal subgroup tend to be asymptomatic as adaptive increases in solute excretion in remaining nephrons compensate for the decline in functioning kidney mass.Oseltamivir is a potent oral antiviral medication that selectively inhibits the influenza neuraminidase enzymes that are essential for viral replication. It is used worldwide for the treatment and prophylaxis of influenza. Oseltamivir is ingested in the form of a prodrug, Oseltamavir phosphate (OP), that is rapidly converted by hepatic esterases into the active metabolite, oseltamivir carboxylate (OC), which is predominately cleared by the kidney via glomerular filtration and active secretion via an organic anion transporter. Mass balance studies have shown that OP is predominately cleared via hepatic conversion to OC with minimal excretion unchanged in urine (<5%) when administered via the oral route. Exposure to OC with the currently approved oral regimen of 75 mg qd in patients with severe renal impairment was approximately 5 fold higher than in patients with normal renal function (CRCL 90-140 ml/min) receiving 75 mg bid.  At the time of drug approval this was considered acceptable due to the wide therapeutic window and safety of OC. However, the availability of lower dose Oseltamivir (Tamiflu) capsules and desire to align oral dosing recommendations with those anticipated for IV oseltamivir, provided an impetus to reassess oral dosing in patients with renal impairment. Previous treatment studies in subjects with normal renal function showed that oseltamivir dosages of 75 mg twice daily result in OC plasma levels sufficient to inhibit neuraminidase enzyme activity from all the tested influenza virus strains.5, 6. Other studies have shown that 75 mg oseltamivir given orally once daily for prophylaxis effectively prevents influenza illness. Although the clinical pharmacokinetic/pharmacodynamic (PK/PD) indices for efficacy and resistance have not yet been clearly identified for Oseltamivir, the plasma PK profiles of OC in patients with varying degrees of renal impairment is aimed to at least match that of the established adult 75 mg BID dose regimen, which showed high efficacy and tolerability, and carried a low risk of generating resistance in phase III studies. In the current analyses, a mixed effects population modeling approach was used to characterize the disposition of OP and OC in subjects with varying degrees of renal impairment but otherwise healthy.

• The decrease in the volume of distribution of the metabolite OC with declining renal function may be rationalized by decreased binding to tissues of the carboxylate anion in renal disease.

• Taking into consideration results of the above modeling and simulation analyses and the criteria for dose selection, the lower dose of 30 mg qd and 30 mg qod can be considered appropriate for treatment and prophylaxis of influenza, respectively, in patients with Severe renal impariemnt (CrCL 10-30 mL/min).

• The lower dose of 30 mg bid and 30 mg qd can be considered appropriate for treatment and prophylaxis of influenza, respectively, in patients with moderate renal impairment (CrCL 30-60 mL/min).

• No dose modification is necessary for patients with mild renal impairment ( CrCL 60-90 mL/min).

Data

Data from eighty subjects, who received various oral dosages of oseltamivir in either single or repeated-dose regimens in 3 separate studies and for whom full PK data sets were available, were used to develop the oseltamivir population PK model (Table I). These combined data provided an informative dataset, with at least nine PK samples collected per subject, providing intensive PK sampling. All studies were performed in accordance with the Declaration of Helsinki. Subjects provided written, informed consent before entering the studies, and the relevant study protocols were approved by the institutional review board at each study site.

Population PK Model

Plasma OP concentration data was initially modeled separately and then OC concentration data was added and analyzed simultaneously. Concentration Time plots of the prodrug OP displayed bi-exponential kinetics whereas OC showed mono-exponential disposition. Under the assumption that OP was predominantely cleared via conversion to the metabolite OC, and that OC was cleared predominantely via the renal route, the basic structural model (Figure 2) consisted of 2 disposition compartments for OP and complete conversion of OP to OC from the central compartment; and a single disposition compartment for OC with a single clearance pathway.

Model development was performed using nonlinear mixed-effects modeling using NONMEM (version VI, level 1.0, GloboMax, Hanover, Maryland). The first order conditional estimation (FOCE) method with Interaction was used for parameter estimation. All simulations were performed in NONMEM. During model building, the goodness-of-fit to the data was evaluated using the following criteria: change in the minimum objective function (MOF), visual inspection of concordance and residual plots, precision of the parameter estimates, and decreases in both inter-individual and residual variability. A decrease in the MOF of at least 10.8 upon addition of a parameter was considered statistically significant. This corresponds to a nominal p-value of at <0.001 and one degree of freedom in the chi-square distribution of the difference of MOF between hierarchical models.

Random Effects

Unexplained intersubject variability in PK model parameters was estimated using the following model with the random effect ηj :

Pj=TVP exp(ηj) Equation I

Where TVP is the typical value of the PK parameter in the population, Pj is the individual value for P in the jth individual, and ηj is a random variable with a mean of zero and a variance ωp2. An additive proportional error model was used to describe random residual variability for both OP and OC.

Covariates

Model PK parameters were plotted against various covariates. Significant covariates on population PK parameters including CRCL were and were added to the base model to develop the final PK model. These were identified using decrease in the MOF criteria during forward addition and backward elimination of the covariate in the full model. Based on inspection of PK parameter vs. covariate plots, covariates were modeled using a linear function with centering on the median of the covariate as shown below for illustration:

TVP = θp + θCRCL(CLCRj – CLCRmed) Equation II

Where TVP is the typical population value of the model parameter, θp is the fixed effects population estimate, θCRCL is the slope of the relationship describing the effect of CRCL on the parameter P, CLCRj is the covariate value of the jth patient, and CLCRmed is the median of the covariate value in the study population.

Model Evaluation

Model evaluation was preformed using diagnostic goodness-of-fit plots including concordance of population and individual predictions with observed OP and OC concentrations as well as residual plots to inspect outliers.Plots were constructed using S-PLUS version 6.2 (Insightful Corporation, Seattle, Washington) A visual predictive check of the final model (with the median, 5th and 95th percentiles) was performed and was stratified via renal function for visual display of the model performance within each renal subgroup.

Simulation of Treatment and Prophylaxis Regimens

One hundred CRCL values were randomly generated from a uniform distribution for each of the mild, moderate, and severe renal impairment subgroups as well as subjects with normal renal function and this data was used to perform simulations in NONMEM. Exposure metrics including Cmax, Cmin, and AUC (normalized to a 48 hr interval) of various regimens were simulated at steady state from the final model for each renally impaired subgroup. Median, 5th and 95th percentiles of the simulations were calculated in addition to box-plots for visual display. The simulated exposures were compared side-by-side to simulated treatment and prophylaxis exposures in subjects with normal renal function. The criteria for selection of a treatment dose included exceeding the Cmin (efficacy coverage) of the established 75 mg bid regimen and not exceeding the 150 mg bid Cmax concentrations produced in subjects with normal renal function.

To re-investigate various treatment and prophylaxis regimens of Oseltamavir and recommend alternative oral dosing regimens for patients with mild, moderate and severe renal impairment that: a) provide homogenous exposure with treatment and prophylaxis regimens in normal subjects b) are hence aligned with those anticipated for the IV formulation.

D

Figure 1. Pharmaockinetic Profiles of OP (Prodrug) and OC (Metabolite) by Study.

Table I. Patient Characteristics

Figure 2. Schematic of the base structural pharmacokinetic model used to describe OP (Parent) and OC (Metabolite) plasma concentrations simultaneously.

Ka is the first order rate of absorption, Vop is the central volume of the Parent OP, Vp is the peripheral volume of OP, Q is an inter-compartmental clearance term, CLop is the clearance of OP, CLoc is the clearance of OC metabolite and Voc is the volume of OC metabolite.

Ka Q/Vop

Q/Vp

CLop/Vop

CLoc/Voc

Central (OP) Vop

Central (OC) Voc

Peripheral (OP) Vp

Oral Depot

Study Study 1 Study 2 Study 3Roche Study Number WP15648 WP15517 WP15525Design Single-center, open-label,

parallel-group renal impairment study

Single-center, double-blind, randomized, placebo-controlled

Single-center, double-blind, randomized, placebo-controlled

Renal Function (mL/min) 4 groups: SEVERE: 10 > CRCL ≤30 mL/min and not on dialysis.MODERATE: 30 > CRCL ≤ 60 mL/min.MILD: 60 > CRCL ≤90 mL/min.NORMAL: CRCL > 90 mL/min

Healthy Volunteers Healthy Volunteers

Oseltamivir Doses Tested 100 mg twice daily for a period of 4 days with a single oral administration OP only on Days 1 and 6

Placebo, 20, 50, 100, 200, 500, 1000 mg single oral OP

Placebo, 50, 100, 200, 500 mg oral twice a day for 7 days OP

Number of volunteers, total, used in model building

20, 20 48, 36 32, 24

CRCL mean±SD (mL/min) SEVERE: 19.6± 5.5MODERATE: 49.6± 10.9MILD: 77.3± 3.9NORMAL: 130.9± 10

107.5±16 104.8±16

CRCL Range (min,max) 12.4, 140 80.3, 140 79.3, 139.6

Mean age ± SD (y) 39.2± 12.7 34.9± 8.8 33.4± 8.6

Mean weight ± SD (kg) 75.3 ± 15.5 78.1 ± 8.5 78.3 ± 12.1

SEX Male:Female 14:6 48:0 32:0

RACE Caucasian:Other 19:1 46:2 32:0

Figure 3. Linear Relationships of PK Parameters vs. Creatinine Clearance

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71717272727272727272

72727272727272

727272727272727272

7272737373

737373737373737373

73

7373737373737373737373

7373

7373

747474747474747474747474

74

74747474747474747474

74747474

74757575757575757575757575

75757575757575757575

7575757575

7676767676767676767676767676767676767676767676767676767677777777777777777777777777

7777777777777777777777777777777878787878787878787878787878787878787878787878787878787879797979797979797979797979

79797979797979797979797979797980808080808080808080808080808080808080808080808080808080

PRED

WR

ES

0 1000 2000 3000

-30

-20

-10

010

2030

111111111111112222222222222333333333333344444444444445555555555555666666666666677777777777777888888888888888999999999999101010101010101010

101010101010111111111111111111111111111112121212121212121212121212121213

1313131313131313131313

1313131314141414141414141414141414141414

151515151515151515151515

151515151616161616161616161616161616161617171717171717171717171717171818181818181818181818181818181919

1919191919191919191919191919

202020202020202020202020202020202021212121212121212121212121212121222222222222222222

2222222222222222232323232323232323232323232323232324242424242424242424242424

24242425 25 25 252525252525252525252525

252526 26 262626262626262626262626262626

2727 27

272727272727272727272727272728

28 282828282828282828282828282828

29

2929 2929292929292929292929292929

3030 30 3030303030

303030303030303030 31 31 31 31 31313131313131313131313131

32 32

32 32 32323232323232323232323232 33 33

33 33333333

3333

33333333

333333

3334

34 34 34 343434

34343434343434343434

3535 35 35 35353535353535353535353535 36 36 36 36 36363636363636363636363636

3737373737373737373737373737373737373737373737373737373737373838383838383838383838383838383838383838383838383838383838383939393939393939393939393939393939393939393939393939393939394040404040404040404040404040404040404040404040404040404040404041414141414141414141414141414141414141414141414141414141414142424242424242424242424242424242424242424242424242424242424243434343434343434343434343434343434343434343434343434343434344444444444444444444444444

44444444444444444444444444444444444445454545454545454545454545454545454545454545454545454545454545464646464646464646464646

46464646464646464646464646464646464647474747474747474747474747474747474747474747474747474747474747

4848484848484848484848484848484848484848484848484848484848484849494949494949494949494949494949494949494949494949494949494949

50

50505050505050505050505050505050505050505050505050505050

505051

515151515151515151515151515151515151515151515151515151515151

52525252525252525252525252525252525252525252525252525252525252

53

53

5353535353535353535353 53

53535353

535353535353535353

53535353

54

54545454545454545454545454545454

545454545454545454545454545455

55 55 55555555555555555555 55555555 55 5555555555555555555555555556

56 56 5656565656565656565656565656

565656

5656565656565656565656

57

57 57 57575757575757575757 57575757 57 5757575757575757575757575758

58 58 58585858585858585858 58585858 58 5858585858585858585858585859

59 59 59595959595959595959 59595959 59 5959595959595959595959595960

60 60 60606060606060606060 60606060 60 60606060606060606060606060

616161616161616161

61

61

61

61

61

61

61

6161

6161616161

616161

61

61

62626262

6262626262

626262

62

6262

62

6262

62626262

6262

62

62

62

62

6363

6363636363636363

63

63

6363

6363

63

6363

63

63

636363

63

6363

63

646464646464646464

646464

64

64

64646464

64646464

64

64

6464

6464

65656565656565656565

65

6565

65

6565656565656565656565

6565

65

666666666666666666666666

6666

66666666666666

666666666666

66

67676767676767676767676767676767

676767676767676767676767

686868686868686868686868686868686868686868686868686868

68

69696969696969696969

69

696969

69

69696969

69696969696969

6969

70707070707070707070707070

7070707070707070707070

707070

7071717171

717171717171717171717171717171717171717171717171727272727272727272727272727272

7272727272727272727272

737373737373737373737373

73

7373737373737373737373737373

73

7474747474747474747474747474747474

747474747474747474

7474757575757575757575757575757575757575757575757575757575

76767676767676767676767676

767676767676767676767676767676

77777777777777777777777777777777777777777777777777777777787878787878787878787878787878787878787878787878787878

78

79

797979797979797979797979797979797979797979797979797979

80808080808080808080808080808080808080808080808080808080

TIME (h)

WR

ES

0 50 100 150

-30

-20

-10

010

2030

1111111111111122222222222223333333333333444444444444455555555555556666666666666777777777777778888888888888889999

99999999101010101010101010101010101010111111111111111111111111111112121212121212121212121212121213

1313131313131313131313

13131313141414141414141414141414141414 14151515151515151515

151515151515 15161616161616161616161616161616161717171717171717171717171717181818181818181818

1818181818181919

1919191919191919191919191919

20202020202020202020202020202020 20212121212121212121212121212121 21222222222222222222222222222222222223232323232323232323232323232323 2324242424242424242424242424

2424 24252525252525252525252525252525

25 2526262626262626262626262626262626 2627272727272727272727272727272727 2728282828282828282828282828282828 2829

292929292929292929292929292929 2930303030303030303030303030303030 3031313131313131313131313131313131 31

3232

3232323232323232323232323232 3233333333333333

3333

33333333

333333

33343434343434343434343434

34343434 3435353535353535353535353535353535 3536363636363636363636363636363636 36373737373737373737373737 37 37 37373737373737373737373737373737383838383838383838383838 38 38 38383838383838383838383838383838393939393939393939393939 39 39 3939393939393939393939393939393940404040404040404040404040 40 40 40404040404040404040404040404040414141414141414141414141 41 41 41414141414141414141414141414141424242424242424242424242 42 42 42424242424242424242424242424242434343434343434343434343 43 43 4343434343434343434343434343434344444444444444444444444444

44 44 4444444444444444444444444444444445454545454545454545454545 45 45 45454545454545454545454545454545464646464646464646464646

46 46 4646464646464646464646464646464647474747474747474747474747 47 47 4747474747474747474747474747474748484848484848484848484848 48 48 4848484848484848484848484848484849494949494949494949494949 49 49 49494949494949494949494949494949

50

50505050505050505050505050

50 5050505050505050505050505050

505051

51515151515151515151515151 51 51515151515151515151515151515151

52525252525252525252525252 52 52 52525252525252525252525252525252

53

53

5353535353535353535353 53

53 535353

535353535353535353

53535353

54

545454545454545454545454 54 54 5454

545454545454545454545454545455555555555555555555555555 55 55 5555555555555555555555555555555556565656565656565656565656

56 56 56565656565656565656565656565656

57

575757575757575757575757 57 57 5757575757575757575757575757575758585858585858585858585858 58 58 5858585858585858585858585858585859595959595959595959595959 59 59 5959595959595959595959595959595960

606060606060606060606060 60 60 60606060606060606060606060606060

616161616161616161

61

61

61

61

61

61

61

6161

6161616161616161

61

61

626262626262626262626262

62

6262

62

6262

62626262

6262

62

62

62

62

6363

636363636363636363

63

6363

6363

63

6363

63

63

636363

63

6363

63

6464646464646464646464

64

64

64

64646464

64646464

64

64

6464

6464

6565656565656565656565

6565

65

6565656565656565656565

6565

65

666666666666666666666666

6666

666666666666666666666666

6666

67676767676767676767676767 67 6767

676767676767676767676767

68686868686868686868686868 68 68

68686868686868686868686868

69696969696969696969

69

696969

69

6969696969696969696969

6969

70707070707070707070707070

70 70707070707070707070707070

7071717171717171717171717171 71 71717171717171717171717171717272727272727272727272 72 727272

7272727272727272727272

737373737373737373

73737373

73 73737373737373737373

73737373

74747474747474747474747474

74 74747474747474747474

74747474

757575757575757575757575

757575757575757575757575757575

76767676767676767676767676

767676767676767676767676767676

7777777777777777777777777777

777777777777777777777777777778787878787878787878787878 78 7878787878787878787878787878

79

797979797979797979797979

79 7979797979797979797979797979

80808080808080808080808080 80 8080808080808080808080808080

Final Model

PRED

OC

Con

c (n

g/m

l)

0 2000 4000 6000

020

0040

0060

00

11111111111111222222222222233333333333334444444444444555555555555566666666666667777777777777788888888888888899999999999910101010101010101010101010101011111111111111111111111111111212121212121212121212121212121313131313131313131313131313131314141414141414141414141414141414151515151515151515151515151515151616161616161616161616161616161617171717171717171717171717171818181818181818181818181818181919

191919191919191919191919191920202020202020202020202020202020202121212121212121212121212121212122

2222222222222222222222222222222223232323232323232323232323

232323232424242424242424242424242424242425

25252525252525252525

2525

2525252526

2626

26262626

2626262626

26

2626262627

2727

27

27

27272727

27

2727

272727272728

2828

28

282828282828

282828

2828282829

2929

29292929292929

2929

292929292930

30303030303030

303030

3030

3030303031

3131

3131313131313131

31

31

3131313132

32

32

32

32

32

3232

3232

32

32

32

3232323233

333333

3333

33

33

33

33

333333

33

33333334

34

34

3434

34

34

34

3434

34

3434

3434

343435

35

35

35

3535353535

3535

3535

35

35353536

3636

36

3636

36363636

36

3636

3636

3636373737373737373737373737373737373737373737373737373737373737383838383838383838383838383838383838383838383838383838383838393939393939393939393939393939393939393939393939393939393939404040404040404040404040404040404040404040404040404040404040404141414141414141414141414141414141414141414141414141414141414242424242424242424242424242424242424242424242424242424242424343434343434343434343434343434343434343434343434343434343434444444444444444444444444444444444444444444444444444444444444445454545454545454545454545454545454545454545454545454545454545464646464646464646464646464646464646464646464646464646464646474747474747474747474747474747474747474747474747474747474747474848484848484848484848484848484848484848484848484848484848484849494949494949494949494949

49494949494949494949494949494949

494950505050505050505050505050

50505050505050505050505050

505050505051

51515151515151515151515151515151

515151515151515151515151515152

525252525252525252525252525252525252525252525252525252525252

5353

53535353535353535353535353535353

535353535353535353

535353535454545454545454545454545454545454

545454545454545454

545454545455

555555555555

5555555555

55

55555555

5555

55555555555555

555555

5555

565656

56565656565656

565656

56565656

5656

56

56

5656

5656

56

5656

56

565657

5757

575757575757

5757

5757

57575757

575757

57575757

5757

5757

5757

5758

5858

5858585858585858

5858

5858585858

585858585858

585858

5858

5858

5959

59

59595959595959

5959

59

59595959

59

59

595959595959

59

5959

59

595960

606060606060

606060

6060

60

60606060

6060

606060606060

60

6060

60

6060

61616161

6161616161616161

61

61

616161

6161

61616161

6161

61

61

61

62626262

62626262626262

62

62

62

62

626262

6262626262

62

6262

62

62

6363

6363636363636363

6363

63

636363

63

636363

63

6363

63

63

63

63

63

646464646464646464646464

64

6464646464

64646464

64

646464

64

64

6565656565656565656565

6565

65

65656565656565656565

6565

65

65

66666666666666666666666666

66

6666666666

66666666

666666

66

66

676767676767676767676767

67

6767676767676767676767676767

67

6868686868686868686868

6868

68686868686868686868

686868

6868696969696969696969

69696969

69

69696969

696969696969

6969

69

69

707070707070707070707070

70

7070707070707070707070

7070

7070

717171717171717171717171

71

71717171717171717171717171

71717272727272727272

727272727272727272727272727272

727272

737373737373737373737373

73

7373737373737373737373

73737373747474747474747474747474

74

7474747474747474747474747474

74757575757575757575757575

75757575757575757575757575

75757676767676767676767676767676767676767676767676767676767677777777777777777777777777

777777777777777777777777777777787878787878787878787878787878787878787878787878787878787979797979797979797979797979797979797979797979797979797980808080808080808080808080808080808080808080808080808080

IPRED

OC

Con

c (n

g/m

l)

0 1000 3000 5000

020

0040

0060

00

11111111111111222222222222233333333333334444444444444555555555555566666666666667777777777777788888888888888899999999999910101010101010101010101010101011111111111111111111111111111212121212121212121212121212121313131313131313131313131313131314141414141414141414141414141414151515151515151515151515151515151616161616161616161616161616161617171717171717171717171717171818181818181818181818181818181919191919191919191919191919191920202020202020202020

2020202020202021212121212121212121212121212121222222222222222222222222222222222223232323232323232323232323

232323232424242424242424242424242424242425

252525252525252525

2525

252525

25252626

26

262626

26

2626262626

26

2626262627

2727

27

27

27272727

27

2727

272727272728

282828

282828282828

282828

2828282829

2929

2929292929

2929

2929

292929292930

3030

3030303030

303030

3030

3030303031

3131

3131313131313131

31

31

31313131

32

32

32

32

32

32

3232

3232

32

32

32

3232323233

3333 33

3333

33

33

33

33

333333

33

33333334

34

34

3434

34

34

34

3434

34

3434

3434

343435

35

35

35

3535353535

3535

3535

35

35353536

3636

36

3636

36363636

36

3636

3636

3636373737373737373737373737373737373737373737373737373737373737383838383838383838383838383838383838383838383838383838383838393939393939393939393939393939393939393939393939393939393939404040404040404040404040404040404040404040404040404040404040404141414141414141414141414141414141414141414141414141414141414242424242424242424242424242424242424242424242424242424242424343434343434343434343434343434343434343434343434343434343434444444444444444444444444444444444444444444444444444444444444445454545454545454545454545454545454545454545454545454545454545464646464646464646464646464646464646464646464646464646464646474747474747474747474747474747474747474747474747474747474747474848484848484848484848484848484848484848484848484848484848484849494949494949494949494949

49494949494949494949494949494949

494950

505050505050505050505050

50505050505050505050505050

5050

50505051515151515151515151

51515151515151

5151515151515151

5151

5151515152525252525252525252525252

525252525252525252525252525252525252

5353

535353535353

535353535353535353

53

5353535353

53535353

535353535454545454545454545454545454545454

545454545454545454

545454545455

555555555555

5555555555

55

55555555

5555

55555555555555

555555

5555

565656

56565656565656565656

56565656

5656

56

56

5656

565656

5656

56

565657

5757575757575757

5757

5757

57575757

575757

57575757

5757

5757

5757

5758

58585858585858585858

5858

5858585858

5858585858585858

58

5858

5858

5959

59

59595959595959

5959

59

59595959

59

59

595959595959

59

5959

59

595960

606060606060

606060

6060

60

60606060

6060

606060606060

60

6060

60

6060

616161616161616161616161

61

61

616161

6161

61616161

6161

61

61

61

6262

6262

62626262626262

62

62

62

62

626262

62626262

6262

6262

62

62

6363

636363636363

636363

6363

636363

63

636363

63

6363

63

63

63

63

63

6464646464646464646464

64

64

6464646464

64646464

64

646464

64

64

6565656565656565656565

6565

65

656565656565656565656565

65

65

66666666666666666666666666

66

6666666666

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Figure 4. Goodness-of-Fit Plots of the Base and Final Population PK Model

Figure 5. Visual Predictive Checks of OP (Prodrug) Concentrations Stratified by Renal Function

Figure 6. Visual Predictive Checks of OC(Metabolite) Concentrations Stratified by Renal Function

Table II. Final Model Pharmacokinetic Parameter Estimates

Parameter Estimate Relative Standard Error (%)

Fixed EffectsCLop (L/h) 620 4

Vop (L) 380 10

Ka (h-1) 0.7 5

Q (L/h) 79.4 12

Vp (L) 1370 12

CLoc (L/h) 22 4

Voc (L) 190 4

Covariate Effects

θCLCR on CLoc 0.24 4

θCLCR on Voc 1.61 9

θCLCR on CLop 2.99 18

Inter-Individual Variability

VAR (ηCLop) (CV%) 32 23

VAR (ηVop) (CV%) 65 19

VAR (ηKa) (CV%) 33 17

VAR (ηCLoc) (CV%) 34 14

VAR (ηVoc) (CV%) 35 18

COV (ηCLop : ηVop), r 0.49 37

COV (ηCLoc : ηVoc), r 0.77 18

Residual Errorσprop,OP (CV%) 40.1 5

σprop,OC (CV%) 17.3 8

Additive Error,OP (ng/ml) 0.76 16

Additive Error,OC (ng/ml) 9.25 32

Renal Function/ Impairment

Mild (CRCL 60-90

ml/min)

Regimen / PK Exposure Parameter 75mg bid1 150mg bid 450mg bid 75 mg bid1 75mg bid1 30 mg bid2 75 mg qd1 30 mg qd2

Cmin (ng/ml)160

(74, 261)298

(123, 576)810

(450,1903)266

(127, 474)574

(228, 1057)229

(110, 500)772

(219,2885)280

(105, 1429)

Cmax (ng/ml)320

(184, 503)629

(329, 1042)1770

(926, 3732)499

(261, 852)955

(395,1477)354

(183, 675)1399

(625, 4118)553

(280, 1953)

AUC0-48 h (ng*hr/ml)11760

(6560, 18760)22680

(11920, 37360)62160

(36640, 136520)18968

(9996, 317852)37840

(15400, 62720)14838

(7206, 29146)54940

(20540, 203560)20900

(9140, 101440)

Moderate (CRCL 30-60 ml/min)

Normal (CRCL 90-140 ml/min)

Severe (CRCL 60-90 ml/min)

Renal Function/ Impairment

Normal (CRCL 90-140

ml/min)

Mild (CRCL 60-90

ml/min)

Regimen / PK Exposure Parameter 75mg qd1 75 mg qd1 75mg qd1 30 mg qd2 75 mg qod1 30 mg qod2

Cmin (ng/ml)40

(14, 75)69

(20, 133)176

(53, 399)68

(25, 179)224

(66, 1485)88

(19, 698)

Cmax (ng/ml)231

(132, 436)342

(193, 608)585

(271, 1121)244

(124, 476)1129

(566, 2789)446

(209, 1280)

AUC0-48 h (ng*hr/ml)5780

(3200, 10640)9000

(5020, 15440)17360

(8020, 37460)7280

(3660, 14980)29330

(13650, 105170)10830

(4090, 49060)

Severe (CRCL 60-90 ml/min)

Moderate (CRCL 30-60 ml/min)

CLop is the clearance of parent OP; Vop is the central volume of OP; Ka is the first order rate of absorption; Q is an inter-compartmental clearance term; Vp is the peripheral volume of OP; CLoc is the clearance of OC metabolite; Voc is the volume of OC ; θ is a parameter describing the relationship between CRCL and a PK parameter, CV% is the percent coefficient of variation; VAR is the variance ; η is the ETA term; COV is the covariance; r is the correlation coefficient; σ is a random effects parameter describing proportional residual error.

Table III. Simulated Median (5th and 95th percentiles) Treatment Exposure Metrics of OC in Normal and Renally Impaired Subjects (N=100)

Figure 7. Box plots of Simulated Cmax and Cmin of OC after administration of various treatment regimens in subjects with severe (upper panels) and moderate (lower panels) renal impairment and normal renal function.

Table IV. Simulated Median (5th and 95th percentiles) Prophylaxis Exposure metrics of OC in Normal and Renally Impaired Subjects (N=100)