In 2022 I was working as a senior pharmacometrician (primarily focused on clinical phase 1/2a PK/PD and scientific research) when I was contacted by a recruiter on LinkedIn to apply for an Associate Director Modelling & Simulation position in the ADME group of the early development (non-clinical) team of a clinical stage pharmaceutical company. The hiring process consisted of a number of interviews and a case study.
As I did not find any real world examples of case studies in the pharmacometrics world online, I wanted to share the contents of my case study here so you can see what was requested and you might want to give it a try yourself to see where you struggle and be better prepared for your own interview!
The following data of the case study was given 7 days in advance of the presentation date. The request was a 45 minute presentation with a 15 minute discussion to the full early development team consisting of ADME, toxicology, and pharmacology experts (no pharmacometricians).
Note: the case study is all based on hypothetical simulated data of a hypothetical compound called D071. Data was changed and questions were slightly altered for this blog post.
Part 1: preclinical PK modeling and human PK predictions
Based on IV and PO data in preclinical species:
- Generate NCA and compartmental PK models for all preclinical species
- Predict oral PK profiles at higher dose levels (30-100-300 mg/kg in rats, 30-100 mg/kg in monkey)
- Predict 2h-IV infusion profiles at 1, 3, 10 mg/h/kg in the preclinical species
- Explain the underlying assumptions used for modeling
- List which experimental data would be necessary to verify / refine those assumptions
Based on in vitro potency on the pharmacological target, and assuming a 2h target coverage:
- Predict efficacious doses (PO/infusion) in preclinical species based on IC90 assuming a vascular target
- Predict efficacious doses (PO/infusion) in preclinical species based on IC90 assuming a target in brain
- Predict human oral and 2h-infusion PK profiles reaching efficacious concentrations as above (loading doses may be applied in the clinic if needed)
- Explain the underlying assumptions used for those predictions
- List which experimental data would be necessary to verify / refine those assumptions
Part 2: PK/PD modeling
Based on PK and efficacy data in monkeys:
- Generate the PK/PD relationship and propose PK/PD target exposures required for efficacy
- Predict human PK/PD
- Predict human efficacious doses via oral and for a 2h IV infusion
Available datasets
Molecular weight of D071
The molecular weight of compound D071 is 438 g/mol.
Male and female rat PK IV bolus / PO, including renal excretion
Male rats
Day 1: D071 @ 1 mg/kg iv (ng/ml plasma) | ||||||
Time (h) | MR1 | MR2 | MR3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 4290 | 2340 | 2650 | 3093,3 | 1047,9 | 33,9 |
0,5 | 2140 | 885 | 1500 | 1508,3 | 627,5 | 41,6 |
1 | 1180 | 260 | 659 | 699,7 | 461,3 | 65,9 |
2 | 567 | 30,1 | 120 | 239,0 | 287,6 | 120,3 |
3 | 378 | 27,1 | 77,9 | 161,0 | 189,6 | 117,8 |
4 | 311 | 31 | 48 | 130,0 | 157,0 | 120,8 |
6 | 181 | 15,4 | 43,2 | 79,9 | 88,7 | 111,0 |
8 | 99,6 | 14,6 | 33,5 | 49,2 | 45 | 90,7 |
10 | 74,6 | 7,89 | 27,5 | 36,7 | 34 | 93,5 |
12 | 51,8 | 5,71 | 21,5 | 26,3 | 23 | 88,9 |
18 | 12,5 | 1,98 | 8,85 | 7,8 | 5 | 68,7 |
24 | 2,17 | 0,546 | 4,71 | 2,5 | 2,1 | 84,8 |
Day 1: D071 @ 1 mg/kg iv | ||||||
MR1 | MR2 | MR3 | Mean | SD | CV% | |
Amount excreted in urine in 12h (%) | 40,2 | 38,1 | 32,6 | 37,0 | 3,9 | 10,6 |
BW (kg) | 0,31 | 0,28 | 0,27 |
Day 7: D071 @ 1 mg/kg po (ng/ml plasma) | ||||||
Time (h) | MR1 | MR2 | MR3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 116 | 113 | 107 | 112,0 | 4,6 | 4,1 |
0,5 | 145 | 167 | 140 | 150,7 | 14,4 | 9,5 |
1 | 336 | 138 | 179 | 217,7 | 104,5 | 48,0 |
2 | 375 | 96,1 | 201 | 224,0 | 140,9 | 62,9 |
3 | 398 | 74,5 | 143 | 205,2 | 170,5 | 83,1 |
4 | 363 | 70,4 | 153 | 195,5 | 150,9 | 77,2 |
6 | 272 | 30,7 | 101 | 134,6 | 124,1 | 92,2 |
8 | 282 | 26 | 64,8 | 124,3 | 138 | 111,0 |
10 | 190 | 13,6 | 44,9 | 82,8 | 94 | 113,6 |
12 | 131 | 8,1 | 31,1 | 56,7 | 65 | 115,2 |
18 | 38,9 | 1,82 | 15,6 | 18,8 | 19 | 99,8 |
24 | 15 | 0,501 | 4,69 | 6,7 | 7,5 | 110,9 |
Day 14: D071 @ 10 mg/kg po (ng/ml plasma) | ||||||
Time (h) | MR1 | MR2 | MR3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 1270 | 1040 | 1100 | 1136,7 | 119,3 | 10,5 |
0,5 | 2080 | 1440 | 1740 | 1753,3 | 320,2 | 18,3 |
1 | 2860 | 1580 | 2240 | 2226,7 | 640,1 | 28,7 |
2 | 2980 | 1340 | 2110 | 2143,3 | 820,5 | 38,3 |
3 | 2580 | 1080 | 1690 | 1783,3 | 754,3 | 42,3 |
4 | 2130 | 881 | 1320 | 1443,7 | 633,6 | 43,9 |
6 | 1400 | 582 | 816 | 932,7 | 421,3 | 45,2 |
8 | 914 | 386 | 518 | 606,0 | 275 | 45,3 |
10 | 591 | 257 | 341 | 396,3 | 174 | 43,8 |
12 | 381 | 172 | 232 | 261,7 | 108 | 41,1 |
18 | 100 | 52,3 | 86,8 | 79,7 | 25 | 30,9 |
24 | 26,1 | 16,3 | 38,3 | 26,9 | 11,0 | 41,0 |
Female rats
Day 1: D071 @ 1 mg/kg iv (ng/ml plasma) | ||||||
Time (h) | FR1 | FR2 | FR3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 1740 | 605 | 242 | 862,3 | 781,5 | 90,6 |
0,5 | 623 | 86,8 | 29,8 | 246,5 | 327,3 | 132,7 |
1 | 127 | 8,63 | 20,3 | 52,0 | 65,2 | 125,5 |
2 | 46,6 | 8,68 | 16,2 | 23,8 | 20,1 | 84,3 |
3 | 41,6 | 4,65 | 9,7 | 18,7 | 20,0 | 107,4 |
4 | 31,7 | 4,29 | 8,02 | 14,7 | 14,9 | 101,3 |
6 | 22 | 2,44 | 3,75 | 9,4 | 10,9 | 116,4 |
8 | 16,4 | 1,57 | 1,42 | 6,5 | 9 | 133,1 |
10 | 6,87 | 0,91 | 0,923 | 2,9 | 3 | 118,5 |
12 | 7,41 | 0,448 | 0,531 | 2,8 | 4 | 142,9 |
18 | 2,08 | 0,157 | LLOQ | |||
24 | 0,916 | LLOQ | LLOQ |
Day 1: D071 @ 1 mg/kg iv | ||||||
FR1 | FR2 | FR3 | Mean | SD | CV% | |
Amount excreted in urine in 12h (%) | 16,1 | 20,0 | 18,0 | 18,0 | 2,0 | 10,8 |
BW (kg) | 0,25 | 0,23 | 0,19 |
Day 7: D071 @ 1 mg/kg po (ng/ml plasma) | ||||||
Time (h) | FR1 | FR2 | FR3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 84 | 37,9 | 234 | 118,6 | 102,5 | 86,4 |
0,5 | 135 | 31,8 | 209 | 125,3 | 89,0 | 71,0 |
1 | 125 | 30,9 | 97,1 | 84,3 | 48,3 | 57,3 |
2 | 132 | 15,5 | 38,1 | 61,9 | 61,8 | 99,9 |
3 | 127 | 18,3 | 12,2 | 52,5 | 64,6 | 123,0 |
4 | 86,7 | 14,9 | 5,48 | 35,7 | 44,4 | 124,5 |
6 | 64,5 | 8,08 | 2,2 | 24,9 | 34,4 | 138,0 |
8 | 40,8 | 3,82 | 0,914 | 15,2 | 22 | 146,5 |
10 | 34,7 | 3,08 | 0,472 | 12,8 | 19 | 149,4 |
12 | 24,3 | 1,11 | 0,214 | 8,5 | 14 | 159,9 |
18 | 5,86 | 0,249 | LLOQ | |||
24 | 2,62 | LLOQ | LLOQ |
Day 14: D071 @ 10 mg/kg po (ng/ml plasma) | ||||||
Time (h) | FR1 | FR2 | FR3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 895 | 474 | 1920 | 1096,3 | 743,7 | 67,8 |
0,5 | 1130 | 496 | 1520 | 1048,7 | 516,8 | 49,3 |
1 | 1140 | 428 | 924 | 830,7 | 365,1 | 43,9 |
2 | 968 | 308 | 355 | 543,7 | 368,2 | 67,7 |
3 | 813 | 222 | 149 | 394,7 | 364,1 | 92,3 |
4 | 682 | 160 | 70,6 | 304,2 | 330,2 | 108,6 |
6 | 479 | 83,8 | 23,1 | 195,3 | 247,6 | 126,8 |
8 | 335 | 44,2 | 10,2 | 129,8 | 179 | 137,5 |
10 | 234 | 23,5 | 5,01 | 87,5 | 127 | 145,4 |
12 | 163 | 12,6 | 2,52 | 59,4 | 90 | 151,4 |
18 | 54,7 | 2,06 | 0,329 | 19,0 | 31 | 162,4 |
24 | 18,1 | 0,362 | LLOQ |
Male monkey PK IV bolus / PO
Day 1: D071 @ 1 mg/kg iv (ng/ml plasma) | ||||||
Time (h) | M1 | M2 | M3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 3410 | 2940 | 2910 | 3086,7 | 280,4 | 9,1 |
0,5 | 2100 | 2000 | 2430 | 2176,7 | 225,0 | 10,3 |
1 | 746 | 1300 | 756 | 934,0 | 317,0 | 33,9 |
2 | 172 | 541 | 137 | 283,3 | 223,8 | 79,0 |
3 | 94,8 | 325 | 46,4 | 155,4 | 148,9 | 95,8 |
4 | 86,1 | 160 | 39,9 | 95,3 | 60,6 | 63,5 |
6 | 55,3 | 88 | 38,7 | 60,7 | 25,1 | 41,3 |
8 | 48,3 | 85,1 | 27,6 | 53,7 | 29 | 54,3 |
10 | 31,5 | 58,3 | 23,2 | 37,7 | 18 | 48,7 |
12 | 20,6 | 47 | 22,6 | 30,1 | 15 | 48,9 |
18 | 4,33 | 20,8 | 9,68 | 11,6 | 8 | 72,4 |
24 | 3,04 | 11,5 | 7,97 | 7,5 | 4,2 | 56,6 |
Day 1: D071 @ 1 mg/kg iv | ||||||
M1 | M2 | M3 | Mean | SD | CV% | |
Amount excreted in urine in 12h (%) | 60,3 | 65,8 | 52,1 | 59,4 | 6,9 | 11,6 |
BW (kg) | 4,2 | 4,3 | 3,8 |
Day 7: D071 @ 1 mg/kg po (ng/ml plasma) | ||||||
Time (h) | M1 | M2 | M3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 275 | 69,2 | 416 | 253,4 | 174,4 | 68,8 |
0,5 | 324 | 102 | 499 | 308,3 | 199,0 | 64,5 |
1 | 422 | 170 | 787 | 459,7 | 310,2 | 67,5 |
2 | 296 | 176 | 478 | 316,7 | 152,1 | 48,0 |
3 | 334 | 119 | 495 | 316,0 | 188,6 | 59,7 |
4 | 213 | 106 | 268 | 195,7 | 82,4 | 42,1 |
6 | 183 | 74,9 | 190 | 149,3 | 64,5 | 43,2 |
8 | 134 | 44,6 | 89,8 | 89,5 | 45 | 50,0 |
10 | 55,3 | 42 | 61,1 | 52,8 | 10 | 18,5 |
12 | 52 | 26,4 | 30,3 | 36,2 | 14 | 38,1 |
18 | 13,1 | 10,2 | 15,3 | 12,9 | 3 | 19,9 |
24 | 5,28 | 3,95 | 9,11 | 6,1 | 2,7 | 43,8 |
Day 14: D071 @ 10 mg/kg po (ng/ml plasma) | ||||||
Time (h) | M1 | M2 | M3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
0,25 | 2680 | 1250 | 3700 | 2543,3 | 1230,7 | 48,4 |
0,5 | 4140 | 2140 | 5500 | 3926,7 | 1690,1 | 43,0 |
1 | 5200 | 3150 | 6440 | 4930,0 | 1661,5 | 33,7 |
2 | 4890 | 3550 | 5330 | 4590,0 | 927,1 | 20,2 |
3 | 4070 | 3140 | 3960 | 3723,3 | 508,2 | 13,6 |
4 | 3340 | 2570 | 2930 | 2946,7 | 385,3 | 13,1 |
6 | 2240 | 1630 | 1640 | 1836,7 | 349,3 | 19,0 |
8 | 1520 | 1050 | 971 | 1180,3 | 297 | 25,1 |
10 | 1030 | 699 | 613 | 780,7 | 220 | 28,2 |
12 | 704 | 486 | 413 | 534,3 | 151 | 28,3 |
18 | 231 | 199 | 175 | 201,7 | 28 | 13,9 |
24 | 77,7 | 94,9 | 94,6 | 89,1 | 9,8 | 11,1 |
Brain:plasma ratio was estimated in monkeys, and was 0.5. The B:P ratio was not variable over time.
PPB in rat, monkey, human
The plasma protein binding (reported as fraction unbound, fu) in plasma is given for the RED and the cross-filtration assays.
fu,plasma (RED) | |||
Species | Male/Female | Concentration (µM) | fu |
Rat | M | 0,1 | 0,1 |
Rat | M | 1 | 0,12 |
Rat | M | 10 | 0,14 |
Rat | F | 0,1 | 0,07 |
Rat | F | 1 | 0,8 |
Rat | F | 10 | 0,13 |
Monkey | M | 1 | 0,08 |
Monkey | F | 1 | 0,08 |
Human | M+F | 0,1 | 0,05 |
Human | M+F | 1 | 0,06 |
Human | M+F | 10 | 0,07 |
fu,plasma (cross-filtration) | |||
Species | Male/Female | Concentration (µM) | fu |
Rat | M | 1 | 0,02 |
Rat | F | 1 | 0,01 |
Monkey | M | 1 | 0,02 |
Human | M+F | 1 | 0,01 |
IC50 on pharmacological target in rat, monkey, human
The IC50 in each of the investigated species are reported. No other information is available at this stage.
Potency on receptor X | |
Species | IC50 (nM) |
Rat | 18 |
Monkey | 80 |
Human | 12 |
Efficacy study in monkey PO
Identical monkeys on a different study day as when PK was sampled.
D071 @ 1 mg/kg PO in monkeys (% change from baseline) | ||||||
Time (h) | M1 | M2 | M3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
2 | 22,7 | 10,4 | 30,8 | 21,3 | 10,3 | 48,2 |
3 | 19,5 | 9,22 | 24,9 | 17,9 | 8,0 | 44,6 |
4 | 16,6 | 7,75 | 19,7 | 14,7 | 6,2 | 42,2 |
6 | 11,8 | 5,24 | 12,1 | 9,7 | 3,9 | 39,9 |
8 | 8,22 | 3,52 | 7,54 | 6,4 | 2,5 | 39,5 |
12 | 3,84 | 1,66 | 3,39 | 3,0 | 1,2 | 38,8 |
D071 @ 10 mg/kg PO in monkeys (% change from baseline) | ||||||
Time (h) | M1 | M2 | M3 | Mean | SD | CV% |
0 | 0 | 0 | 0 | 0,0 | 0,0 | – |
2 | 70,7 | 66,5 | 71,7 | 69,6 | 2,8 | 4,0 |
3 | 68,4 | 64,6 | 68 | 67,0 | 2,1 | 3,1 |
4 | 65,6 | 61,4 | 63,5 | 63,5 | 2,1 | 3,3 |
6 | 59 | 52,9 | 53 | 55,0 | 3,5 | 6,4 |
8 | 51,4 | 43,7 | 42,1 | 45,7 | 5,0 | 10,9 |
12 | 35,3 | 28 | 25 | 29,4 | 5,3 | 18,0 |
Note 1: No software environment for modelling or data analysis is provided. Open source software should preferably be used.
Note 2: As it is a case study for learning purposes, no ‘answers’ will be provided.
My personal opinion is that this case study was quite a bit of work to be done in a less than 7-day time period outside of my normal job without a modelling platform, and therefore some corners had to be cut in the analysis. This was also a good learning opportunity for me to try and reduce this work into smaller sections and highlight the key answers and limitations while still being able to show what I can do and how I would handle these questions, even if someone else would have a different approach. If you have looked at my other posts, you would not be surprised that I also created a Shiny application to show additional dosing scenarios during my presentation to the team.
p.s. I got the job in the end.
What are your thoughts on this case study? Did you have a similar case study story you would like to share? Feel free to leave a comment!
Any suggestions or typo’s? Leave a comment or contact me at info@pmxsolutions.com!