ADDENDUM TO THE OFFICE OF CLINICAL PHARMACOLOGY REVIEW NDA: 202895 NDA: 21976 (SDN 201, S-20) Brand Name

Generic Name Reviewer Pharmacometrics Reviewer Pharmacometrics Team Leader Clinical Pharmacology Team Leader OCP Division OND Division Applicant Formulation; strength(s) to-be-marketed Currently marketed formulations Proposed darunavir suspension or tablet dosage regimens coadministered with ritonavir solution Submission Date: March 30, 2011 Submission Date: June 28, 2011 Prezista Darunavir Stanley Au, Pharm.D., BCPS Jiang Liu, Ph.D. Pravin Jadhav, Ph.D. Sarah Robertson, Pharm.D. Division of Clinical Pharmacology 4 Division of Antiviral Products Tibotec, Inc. Darunavir oral suspension (100 mg/mL) Darunavir tablets; 75 mg, 150 mg, 400 mg, 600 mg Twice daily dosing with food: 10 kg to less than 15 kg: Darunavir 20 mg/kg coadministered with ritonavir 3 mg/kg (revised dosage regimen) using darunavir suspension (b) (4) 15 kg to less than : 375 mg (3.8 mL) of darunavir coadministered with 50 mg (0.6 mL) of ritonavir using darunavir tablets or suspension Treatment of HIV-1 infection in pediatric patients 3 to less than 6 years old New Drug Application for darunavir suspension formulation, priority review (NDA 202895) Labeling supplement (NDA 21976, SDN 201)

Proposed Indication for the Application Review Type(s)

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Subsequent to the finalization of the Clinical Pharmacology review for NDA 202895 (with the accompanying labeling supplement for NDA 21976), a number of additional review related issues occurred. The issues are discussed below. 1) Revised darunavir dosage regimen The darunavir review team concluded that for HIV-1 infected pediatric patients weighing 10 kg to 15 kg, darunavir 20 mg/kg coadministered with ritonavir 3 mg/kg twice daily was the most appropriate dosage regimen. The Clinical Pharmacology secondary review (September 27, 2011) discusses the rationale for this decision. 2) Revised population PK analysis for the TMC114-C228 trial The applicant provided additional information regarding the population pharmacokinetic (PK) analysis that was conducted for the TMC114-C228 trial in September 2011. For the visit two weeks after dosage adjustment (Visit 105), the body weight was not recorded unless this visit occurred at a scheduled visit. If a subjects weight was not recorded, the weight that was to be used was the weight recorded at the dosage adjustment visit (Visit 104). However, the applicant noted that due to a data analysis error, if a weight was not available for Visit 105, the subjects last available weight for the analysis dataset was used instead of the last available weight before Visit 105. Because the darunavir population PK model includes body weight as a covariate, corrected population PK parameters were derived. For the corrected darunavir population PK analysis for the TMC 114-C228 trial, the subjects weight for Visit 105 that was included in the dataset was either the actual weight for the visit (Visit 105) or the weight during the dosage adjustment visit (Visit 104). For each subject, the difference in the weight that was used in the original and corrected analysis for the visit two weeks after dosage adjustment (Visit 105) was 10% or less (see Table 1). In the revised population analysis, subjects 9 and 21 that were originally included in the 15 kg to < 20 kg weight group were included in the 10 kg to < 15 kg weight group.

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was the storage of darunavir and ritonavir plasma samples at-70C instead of -20C at the clinical trial sites. The applicant had previously stated that all plasma samples were stored at -20C. To date, the long term stability data for darunavir and ritonavir plasma samples has been generated at -20C only. In response to comments from the Clinical Pharmacology reviewer, the following information in Table 3 was provided regarding the storage of plasma samples at-70C instead of -20C at the trial sites. In response to comments from the Division of Antiviral Products, the applicant stated that -70C long term sample stability data would be generated for up to one year with submission of 70C long term sample stability data for 37 days by December 15, 2011. The data was not available at the time the addendum was finalized. With the exclusion of plasma samples from the Kimuati clinical trial site (KE00004), the longest duration that plasma samples were stored at -70C was 7 days. Overall, the storage of plasma samples at -70C for up to 7 days is not anticipated to significantly impact the reported darunavir and ritonavir plasma concentrations for the TMC114-C228 trial. Table 3-Information regarding storage of darunavir/ritonavir plasma samples at -70 C at clinical trials sites

Reviewer note: There was one sample with a storage time that could not be determined. The clinical trial site that this sample was stored at was not specified by the applicant. 4) Revised population PK analysis data for the TMC114-C228 trial and revisions to the darunavir U.S. prescribing information The applicant provided updated tables and figures below for the TMC114-C228 trial that include the changes discussed in sections 2 and 3 of this addendum.
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A) Pre dose adjustment week 2 population PK analysis The applicant did not provide updated week 2 population PK parameters for the pre dose adjustment week 2 population PK analysis (darunavir 20 mg/kg combined with ritonavir 3 mg/kg twice daily). Reviewer note: 1) On page 39 of the original Clinical Pharmacology review for NDA 202895, subject 33, not subject 30, was excluded because the ritonavir plasma concentrations were all below the lower limit of quantification. B) Post dose adjustment (2 weeks after dose adjustment) population PK analysis Table 4-Corrected darunavir population PK analysis results from the Week 24 analysis for the adjusted dosage regimen 2 weeks after dose adjustment (darunavir 25 mg/kg combined with ritonavir 3 mg/kg twice daily [10 kg to <15 kg and 380 mg of darunavir combined with 50 mg of ritonavir twice daily [15 kg to < 20 kg])

Reviewer note: 1) For the post dose adjustment (2 weeks after dose adjustment) population PK analysis that was generated for the Data Safety Monitoring Board (DSMB) and the analysis presented in Table 4, the same subjects were excluded with one exception: instead of excluding subject 38 that did not have a AAG concentration measured by the central laboratory, subject 15 was excluded from the DSMB analysis due to a data management error.

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Table 5-Original darunavir population PK analysis results derived from the Week 24 analysis for the adjusted dosage regimen 2 weeks after dose adjustment (darunavir 25 mg/kg combined with ritonavir 3 mg/kg twice daily [10 kg to <15 kg and 375 mg of darunavir combined with 50 mg of ritonavir twice daily [15 to < 20 kg])

Reviewer note: In the original Clinical Pharmacology review for NDA 202895, the corresponding table is Table 15, page 41. C) Population PK analysis for the initial dosage regimens Table 6-Corrected darunavir population PK analysis results for the initial dosage regimen (darunavir 20 mg/kg combined with ritonavir 3 mg/kg twice daily)

Reviewer note: The population PK analysis includes the pharmacokinetic data from weeks 2 and 4.

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Table 7-Original darunavir population PK analysis results for the initial dosage regimen (darunavir 20 mg/kg combined with ritonavir 3 mg/kg twice daily)

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Reviewer notes: 1) The units in the table should be g/mL*hr for AUC(0-12h). 1) The population PK analysis includes the pharmacokinetic data from weeks 2 and 4. 2) In the original Clinical Pharmacology review for NDA 202895, the corresponding table is Table 17, page 42. D) Population PK analysis for the adjusted dosage regimens Table 8-Corrected darunavir population PK analysis results for the adjusted dosage regimen (darunavir 25 mg/kg combined with ritonavir 3 mg/kg twice daily [10 kg to <15 kg and 380 mg of darunavir combined with 50 mg of ritonavir twice daily [15 to < 20 kg])

Reviewer note: 1) The population PK analysis includes the pharmacokinetic data from 2 weeks after dosage adjustment and week 24. 2) The following additional subjects were excluded: 5, 10, 14, 18 and 42.

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Table 9-Original darunavir population PK analysis results for the adjusted dosage regimen (darunavir 25 mg/kg combined with ritonavir 3 mg/kg twice daily [10 kg to <15 kg and 380 mg of darunavir combined with 50 mg of ritonavir twice daily [15 to < 20 kg])

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Reviewer notes: 1) The population PK analysis includes the pharmacokinetic data from 2 weeks after dosage adjustment and week 24. 2) In the original Clinical Pharmacology review for NDA 202895, the corresponding table is Table 19, page 43. E) Exposure-response information Figure 1-Corrected darunavir analysis for the comparison of AUC(0-12h) and C0h (for the adjusted darunavir dosage regimens) for subjects either achieving virologic response or not achieving virologic response (HIV-1 RNA less than 50 copies/mL)

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Figure 2-Original darunavir analysis for the comparison of AUC(0-12h) and C0h (for the adjusted darunavir dosage regimens) for subjects either achieving virologic response or not achieving virologic response (HIV-1 RNA less than 50 copies/mL)

Reviewer note: In the original Clinical Pharmacology review for NDA 202895, the corresponding figures are Figure 3 (page 9), and Figure 3 (page 47).

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Table 10-Corrected comparison of the mean darunavir AUC(0-12h) values prior to and subsequent to the adjustment of the darunavir dosage regimens to the mean target adult exposure (including the original and corrected analysis)

Reviewer notes: 1) The mean AUC(0-12h) values in Tables 6 through 9 are compared to the mean adult target exposure of 62.3 g/mL*hr 2) The mean of the median individual darunavir AUC(0-12h) values are compared. 3) The higher percentage difference in AUC(0-12h) for the 10 kg to < 15 group with the revised analysis is not attributed to a significant change in AUC values for individual subjects(see Table 2). Table 11-Original comparison of the mean darunavir AUC(0-12h) values prior to and subsequent to the adjustment of the darunavir dosage regimens to the mean target adult exposure

Reviewer notes: 1) The mean AUC(0-12h) values in Tables 7 and 9 are compared to the mean adult target exposure of 62.3 g/mL*hr. 2) The mean of the median individual darunavir AUC(0-12h) values are compared. 3) In the original Clinical Pharmacology review for NDA 202895, the corresponding tables are Table 9 (page 8), and Table 20 (page 44).

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F) Changes to the proposed revisions for the darunavir U.S. prescribing information (Table 11) Table 12-Orginal proposed population PK parameters for the TMC114-C228 trial using the original population PK analysis Table 11: Population Pharmacokinetic Estimates of Darunavir Exposure (Study TMC114-C212 and Study TMC114-C228) Following Administration of Doses in Tables 1 and 2

Table 13-Final proposed population PK parameters that are included in Table 11 for the TMC114-C228 trial incorporating the changes discussed in the addendum Table 11: Population Pharmacokinetic Estimates of Darunavir Exposure (Study TMC114-C212 and Study TMC114-C228) Following Administration of Doses in Tables 1 and 2

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The revised Table 11 in the darunavir U.S prescribing information is acceptable with the exception of the recommended change to one of the footnotes displayed below if the footnote is meant to convey that the same subjects may be included in both the 10 kg to (b) <15 weight group and the 15 kg to < (4) kg weight group.
(b) (4)

Revised Text Subjects may have contributed PK data to both the 10 kg to < 15 kg (b) weight group and the 15 kg to < (4) kg weight group.

5) Conclusions Overall, the changes that were made to the population pharmacokinetic analysis, the (b) (4) storage of darunavir and ritonavir plasma samples at instead of -20C at the clinical trial sites, and the exclusion of subjects from the Kimuati clinical trial site for the TMC114-C228 trial that are discussed in this addendum do not change the reviewers conclusions for the exposure-response or exposure-safety information from the TMC114C228 trial.

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--------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------STANLEY AU 12/08/2011 SARAH M ROBERTSON 12/08/2011

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