Simultaneous Pharmacogenetics-Based Population Pharmacokinetic Analysis of Darunavir and Ritonavir in HIV-Infected Patients

José Moltó,1,2 George Xinarianos,3 Cristina Miranda,1 Sudeep Pushpakom,3 Samandhy Cedeño,4 Bonaventura Clotet,1,2,4 Andrew Owen,3 Marta Valle,2,5

1Fundació Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

2Universitat Autónoma de Barcelona, Barcelona, Spain

3Department of Molecular and Clinical Pharmacology, University of Liverpool, UK

4Fundació IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

5PKPD modeling and simulation, Institut de Recerca HSCSP-IIB StPau, Barcelona, Spain

Supplementary Table SI: Genetic and allelic frequencies of the SNPs tested in the analysis population.

Alleles / Genotype frequency (%) / Allele frequency (%)
Gene / rs# / Genotype call rate (%) / p / q / pp / pq / qq / p / q
ABCB1 / rs2032582 / 87.8 / G / T / 41.7 / 58.3 / 0 / 70.85 / 29.15
rs1128503 / 58.5 / T / C / 41.7 / 58.3 / 0 / 70.85 / 29.15
ABCC2 / rs2273697 / 95.1 / G / A / 61.5 / 35.8 / 2.7 / 79.4 / 20.6
NR1I2 / rs2472677 / 65.9 / T / C / 100 / 0 / 0 / 100 / 0
rsrs1523130 / 87.8 / G / A / 47.2 / 44.5 / 8.3 / 69.45 / 30.55
rs6785049 / 85.4 / A / G / 40 / 57.1 / 2.9 / 68.55 / 31.45
rs763645 / 87.8 / T / C / 27.8 / 58.3 / 13.9 / 56.95 / 43.05
NR1I3 / rs2307424 / 95.1 / C / T / 46.2 / 46.1 / 7.7 / 69.25 / 30.75
SLCO1A2 / rs5488 / 95.1 / A / T / 2.6 / 20.5 / 76.9 / 12.85 / 87.15
rs2045938 / 87.8 / T / C / 5.6 / 41.6 / 52.8 / 26.4 / 73.6
rs2199688 / 53.7 / C / A / 4.5 / 31.9 / 63.6 / 20.45 / 79.55
rs4148988 / 82.9 / G / A / 17.6 / 44.2 / 38.2 / 39.7 / 60.3
rs4149005 / 87.8 / C / A / 61.1 / 33.3 / 5.6 / 77.75 / 22.25
rs7967902 / 82.9 / C / A / 0 / 44.1 / 55.9 / 22.05 / 77.95
rs10841795 / 95.1 / G / A / 2.6 / 33.3 / 64.1 / 19.25 / 80.75
rs11568557 / 82.9 / C / G / 100 / 0 / 0 / 100 / 0
rs12809573 / 92.7 / C / T / 100 / 0 / 0 / 100 / 0
rs12818993 / 90.2 / G / G / 73 / 27 / 0 / 86.5 / 13.5
rs4762818 / 97.6 / G / A / 77.5 / 20 / 2.5 / 87.5 / 12.5
rs10770805 / 80.5 / A / T / 6.1 / 30.3 / 63.6 / 21.25 / 78.75
rs10841798 / 95.1 / G / T / Fail / Fail / Fail / Fail / Fail
rs11836945 / 95.1 / A / C / 100 / 0 / 0 / 100 / 0
SLCO1B1 / rs976754 / 82.9 / T / C / 61.8 / 32.3 / 5.9 / 77.95 / 22.05
rs999278 / 92.7 / C / A / 42.1 / 44.7 / 13.2 / 64.45 / 35.55
rs2061903 / 95.1 / C / T / 97.4 / 2.6 / 0 / 98.7 / 1.3
rs2306283 / 75.6 / T / C / 12.9 / 67.7 / 19.4 / 46.75 / 53.25
rs3829306 / 97.6 / G / A / 75 / 25 / 0 / 87.5 / 12.5
rs4149034 / 97.6 / G / A / 27.5 / 52.5 / 20 / 53.75 / 46.25
rs4149038 / 95.1 / G / A / 5.1 / 43.6 / 51.3 / 26.9 / 73.1
rs4149056 / 92.7 / T / C / 84.2 / 15.8 / 0 / 92.1 / 7.9
rs4149064 / 95.1 / G / A / 0 / 5.1 / 94.9 / 2.55 / 97.45
rs4149087 / 90.2 / G / T / 8.1 / 54.1 / 37.8 / 35.15 / 64.85
rs4762698 / 82.9 / A / G / 0 / 20.6 / 79.4 / 10.3 / 89.7
rs7962588 / 87.8 / C / G / 22.2 / 61.1 / 16.7 / 52.75 / 47.25
rs11045796 / 95.1 / G / A / 5.1 / 28.2 / 66.7 / 19.2 / 80.8
rs11045819 / 95.1 / C / A / 59 / 35.9 / 5.1 / 76.95 / 23.05
rs11045889 / 85.4 / A / T / 45.7 / 48.6 / 5.7 / 70 / 30
SLCO1B3 / rs975657 / 95.1 / G / A / 7.7 / 59 / 33.3 / 37.2 / 62.8
rs4149117 / 92.7 / G / T / 78.9 / 21.1 / 0 / 89.45 / 10.55
rs10770757 / 85.4 / C / A / 2.9 / 20 / 77.1 / 12.9 / 87.1
rs11045585 / 90.2 / G / A / 2.7 / 18.9 / 78.4 / 12.15 / 87.85
rs17674085 / 78.0 / T / C / 3.1 / 28.1 / 68.8 / 17.15 / 82.85
rs2138334 / 70.7 / G / A / 17.2 / 51.8 / 31 / 43.1 / 56.9
rs7970514 / 82.9 / C / T / 64.7 / 32.4 / 2.9 / 80.9 / 19.1
SLCO1C1 / rs952658 / 92.7 / T / C / 5.3 / 57.9 / 36.8 / 34.25 / 65.75
rs2056136 / 92.7 / A / G / 63.2 / 36.8 / 0 / 81.6 / 18.4
rs10444412 / 92.7 / C / T / 18.4 / 47.4 / 34.2 / 42.1 / 57.9
rs10505868 / 90.2 / T / C / 51.4 / 45.9 / 2.7 / 74.35 / 25.65
rs10770704 / 85.4 / T / C / 8.6 / 54.3 / 37.1 / 35.75 / 64.25
rs10841596 / 92.7 / C / A / 92.1 / 7.9 / 0 / 96.05 / 3.95
rs11045408 / 92.7 / C / G / 100 / 0 / 0 / 100 / 0
rs12820079 / 90.2 / C / G / 10.8 / 54.1 / 35.1 / 37.85 / 62.15
SLCO2A1 / rs2370512 / 97.6 / A / T / 5 / 32.5 / 62.5 / 21.25 / 78.75
rs4327389 / 82.9 / C / A / 29.4 / 53 / 17.6 / 55.9 / 44.1
rs7630191 / 90.2 / C / G / 13.5 / 46 / 40.5 / 36.5 / 63.5
rs9820625 / 80.5 / C / A / 12.1 / 51.5 / 36.4 / 37.85 / 62.15
rs9855403 / 97.6 / A / T / 77.5 / 15 / 7.5 / 85 / 15
rs11720843 / 80.5 / G / T / 66.7 / 33.3 / 0 / 83.35 / 16.65
rs13067921 / 46.3 / C / T / 63.2 / 26.3 / 10.5 / 76.35 / 23.65
rs13093879 / 56.1 / C / A / 60.9 / 39.1 / 0 / 80.45 / 19.55
SLCO2B1 / rs2306168 / 90.2 / C / T / 94.6 / 5.4 / 0 / 97.3 / 2.7
rs2851069 / 82.9 / T / C / 11.8 / 58.8 / 29.4 / 41.2 / 58.8
rs4944993 / 80.5 / G / T / 51.5 / 39.4 / 9.1 / 71.2 / 28.8
rs11236359 / 82.9 / A / G / 0 / 17.6 / 82.4 / 8.8 / 91.2
rs11236365 / 95.1 / T / C / 51.3 / 43.6 / 5.1 / 73.1 / 26.9
SLCO3A1 / rs8174 / 97.6 / G / A / 50 / 42.5 / 7.5 / 71.25 / 28.75
rs207960 / 90.2 / G / T / 59.5 / 35.1 / 5.4 / 77.05 / 22.95
rs207961 / 97.6 / G / C / 37.5 / 47.5 / 15 / 61.25 / 38.75
rs908654 / 95.1 / C / A / 5.1 / 30.8 / 64.1 / 20.5 / 79.5
rs1400784 / 92.7 / A / G / 18.4 / 73.7 / 7.9 / 55.25 / 44.75
rs1400786 / 90.2 / C / A / 0 / 18.9 / 81.1 / 9.45 / 90.55
rs1517618 / 95.1 / G / C / 71.8 / 28.2 / 0 / 85.9 / 14.1
rs1878556 / 97.6 / G / T / 10 / 37.5 / 52.5 / 28.75 / 71.25
rs2048945 / 97.6 / A / T / 50 / 45 / 5 / 72.5 / 27.5
rs2074886 / 92.7 / G / C / 44.7 / 47.4 / 7.9 / 68.4 / 31.6
rs2283453 / 97.6 / G / A / 5 / 37.5 / 57.5 / 23.75 / 76.25
rs2283462 / 90.2 / C / T / 16.2 / 51.4 / 32.4 / 41.9 / 58.1
rs2387398 / 90.2 / A / G / 5.4 / 16.2 / 78.4 / 13.5 / 86.5
rs2892291 / 0.0 / C / G / Fail / Fail / Fail / Fail / Fail
rs3924426 / 95.1 / T / C / 94.9 / 5.1 / 0 / 97.45 / 2.55
rs4777728 / 95.1 / G / A / 2.7 / 5 / 92.3 / 5.2 / 94.8
rs4777789 / 95.1 / G / T / 15.4 / 43.6 / 41 / 37.2 / 62.8
rs4932582 / 95.1 / C / T / 84.6 / 12.7 / 2.7 / 90.95 / 9.05
rs4932587 / 87.8 / G / A / 50 / 41.7 / 8.3 / 70.85 / 29.15
rs4932593 / 97.6 / G / A / 27.5 / 42.5 / 30 / 48.75 / 51.25
rs4932597 / 90.2 / G / A / 0 / 21.6 / 78.4 / 10.8 / 89.2
rs4932598 / 97.6 / C / T / 0 / 22.5 / 77.5 / 11.25 / 88.75
rs4984325 / 73.2 / T / C / 3.3 / 26.7 / 70 / 16.65 / 83.35
rs6496877 / 95.1 / G / A / 53.8 / 33.4 / 12.8 / 70.5 / 29.5
rs8027174 / 100.0 / G / T / 78.7 / 17.3 / 4 / 87.35 / 12.65
rs8032914 / 97.6 / C / T / 60 / 37.5 / 2.5 / 78.75 / 21.25
rs10444880 / 97.6 / T / C / 52.5 / 42.5 / 5 / 73.75 / 26.25
rs11074036 / 78.0 / A / G / 28.1 / 56.3 / 15.6 / 56.25 / 43.75
rs12101522 / 75.6 / G / A / 3.2 / 48.4 / 48.4 / 27.4 / 72.6
rs12708589 / 87.8 / T / C / 13.9 / 47.2 / 38.9 / 37.5 / 62.5
rs12899011 / 95.1 / C / T / 76.9 / 20.5 / 2.6 / 87.15 / 12.85
rs12899055 / 90.2 / T / C / 8.1 / 32.4 / 59.5 / 24.3 / 75.7
rs12909480 / 87.8 / C / T / 61.1 / 33.3 / 5.6 / 77.75 / 22.25
rs12910142 / 78.0 / A / G / 0 / 28.1 / 71.9 / 14.05 / 85.95
rs16974269 / 92.7 / T / A / 7.9 / 26.3 / 65.8 / 21.05 / 78.95
rs17518659 / 95.1 / T / C / 84.6 / 15.4 / 0 / 92.3 / 7.7
rs17597283 / 97.6 / G / A / 72.5 / 25 / 2.5 / 85 / 15
rs4244909 / 87.8 / G / C / 33.3 / 47.3 / 19.4 / 56.95 / 43.05
rs4294800 / 100.0 / A / G / 5.3 / 42.7 / 52 / 26.65 / 73.35
rs4932596 / 95.1 / G / A / 5.1 / 20.5 / 74.4 / 15.35 / 84.65
rs11854488 / 92.7 / C / G / 13.2 / 44.7 / 42.1 / 35.55 / 64.45
rs12912997 / 43.9 / G / T / 27.8 / 72.2 / 0 / 63.9 / 36.1
SLCO4A1 / rs4809464 / 48.8 / T / C / 0 / 66.7 / 33.3 / 33.35 / 66.65
rs6062689 / 97.6 / G / A / 40 / 47.5 / 12.5 / 63.75 / 36.25
rs6122080 / 87.8 / G / A / 22.2 / 47.2 / 30.6 / 45.8 / 54.2
SLCO4C1 / rs709372 / 87.8 / A / G / 50 / 38.9 / 11.1 / 69.45 / 30.55
rs841931 / 97.6 / C / T / 17.5 / 42.5 / 40 / 38.75 / 61.25
rs2263376 / 87.8 / A / G / 0 / 36.1 / 63.9 / 18.05 / 81.95
rs2600833 / 85.4 / A / G / 5.7 / 62.9 / 31.4 / 37.15 / 62.85
rs3096196 / 92.7 / A / G / 65.8 / 34.2 / 0 / 82.9 / 17.1
rs6884301 / 85.4 / T / C / 0 / 51.4 / 48.6 / 25.7 / 74.3
rs7719298 / 100.0 / C / T / 2.7 / 24 / 73.3 / 14.7 / 85.3
rs10057361 / 73.2 / G / T / 0 / 50 / 50 / 25 / 75
rs10515324 / 92.7 / T / A / 0 / 39.5 / 60.5 / 19.75 / 80.25
SLCO5A1 / rs2380563 / 92.7 / G / T / 92.1 / 7.9 / 0 / 96.05 / 3.95
rs2380573 / 87.8 / T / C / 55.6 / 38.8 / 5.6 / 75 / 25
rs2380606 / 7.3 / T / C / Fail / Fail / Fail / Fail / Fail
rs2860461 / 53.7 / T / C / 31.8 / 59.1 / 9.1 / 61.35 / 38.65
rs2933053 / 92.7 / T / C / 26.3 / 47.4 / 26.3 / 50 / 50
rs2933055 / 90.2 / C / T / 48.6 / 27.1 / 24.3 / 62.15 / 37.85
rs2959552 / 97.6 / C / G / 0 / 17.5 / 82.5 / 8.75 / 91.25
rs2959561 / 68.3 / T / C / 28.6 / 46.4 / 25 / 51.8 / 48.2
rs2959566 / 97.6 / C / T / 20 / 50 / 30 / 45 / 55
rs2959580 / 0.0 / C / G / Fail / Fail / Fail / Fail / Fail
rs3750268 / 80.5 / C / A / 51.5 / 42.4 / 6.1 / 72.7 / 27.3
rs4507768 / 90.2 / A / G / 24.3 / 37.9 / 37.8 / 43.25 / 56.75
rs10090896 / 75.6 / A / G / 3.2 / 29.1 / 67.7 / 17.75 / 82.25
rs10112770 / 70.7 / A / G / 100 / 0 / 0 / 100 / 0
rs10504461 / 92.7 / C / T / 94.7 / 5.3 / 0 / 97.35 / 2.65
rs13268590 / 95.1 / G / A / 71.8 / 23.1 / 5.1 / 83.35 / 16.65
rs16936346 / 92.7 / C / T / 0 / 21.1 / 78.9 / 10.55 / 89.45
rs17731173 / 95.1 / T / A / 5.1 / 10.3 / 84.6 / 10.25 / 89.75
SLCO6A1 / rs1901515 / 92.7 / G / A / 23.7 / 50 / 26.3 / 48.7 / 51.3
rs2400796 / 87.8 / T / C / 41.7 / 47.2 / 11.1 / 65.3 / 34.7
rs6873738 / 97.6 / C / A / 47.5 / 40 / 12.5 / 67.5 / 32.5
rs6884141 / 68.3 / A / G / 7.1 / 46.5 / 46.4 / 30.35 / 69.65
rs7356787 / 78.0 / A / G / 12.5 / 46.9 / 40.6 / 35.95 / 64.05
rs10038730 / 0.0 / A / T / Fail / Fail / Fail / Fail / Fail
rs10479213 / 95.1 / C / G / 0 / 12.8 / 87.2 / 6.4 / 93.6
rs12658397 / 87.8 / T / C / 55.6 / 36.1 / 8.3 / 73.65 / 26.35

Suppplementary Figure SI.Mean darunavir concentration profile simulated for each genotype.

* denotes reference genotype