A pharmacometrician’s job interview: the 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.

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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

Good luck!

Available datasets

Molecular weight of D071

The molecular weight of compound D071 is 438 g/mol.

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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

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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.

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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

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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

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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

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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.

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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.

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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!

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