Simulaite Report

Bioavailability Simulation — Kalmegh (Andrographis paniculata) Extract Capsule

March 11, 2026

Executive Summary

We simulated oral bioavailability (F) for diterpene lactone compounds in a standardized Kalmegh (Andrographis paniculata) extract capsule using our Simulaite engine with AI-powered pharmacokinetic modeling on a virtual population of 100 individuals (Asian demographics). Four scenarios were compared: fed state with full extract, fasted state with full extract, fed state with full extract plus piperine bioenhancer, and fed state with andrographolide alone (to quantify the extract’s synergistic bioenhancement effect).

Synergistic extract bioenhancement is the dominant mechanism: andrographolide alone achieves only 10.0% F, but within the full extract reaches 29.2% F — a 2.9× boost from co-extracted flavonoids inhibiting CYP3A4 and reducing P-gp efflux
Piperine provides only a modest additional lift of 1.05× on top of the extract's own bioenhancement (29.2% to 30.6%)
Food effect is minimal for andrographolide (1.03×) but significant for 14-Deoxy-DHA (1.3×), attributed to bile salt solubilization of the less water-soluble dehydro compound

Key Takeaways

Population variability ranges from CV 36–49% for the diterpene lactones in the full extract, but rises to CV 53% when andrographolide is administered alone — the synergistic enhancement stabilizes inter-individual variability

Molecules

Name	SMILES
Andrographolide	C[C@@]12CC[C@H]([C@@]([C@H]1CCC(=C)[C@H]2C/C=C/3\[C@@H](COC3=O)O)(C)CO)O
Neoandrographolide	C[C@]1(CCC[C@@]2([C@@H]1CCC(=C)[C@H]2CCC3=CCOC3=O)C)CO[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O
14-Deoxy-11,12didehydroandrographolide	C[C@@]12CC[C@H]([C@@]([C@H]1CCC(=C)[C@H]2/C=C/C3=CCOC3=O)(C)CO)O
14-Deoxyandrographolide	C[C@@]12CC[C@H]([C@@]([C@H]1CCC(=C)[C@H]2CCC3=CCOC3=O)(C)CO)O
7-O-Methylwogonin	COC1=C(C2=C(C(=C1)O)C(=O)C=C(O2)C3=CC=CC=C3)OC

Name	SMILES
Skullcapflavone I	COC1=C(C2=C(C(=C1)O)C(=O)C=C(O2)C3=CC=CC=C3O)OC
Piperine	C1CCN(CC1)C(=O)/C=C/C=C/C2=CC3=C(C=C2)OCO3

We use our suite of graph neural networks to predict relevant molecular properties and interactions with liver enzymes, plasma proteins, and the gut wall to inform the simulations.

Extracts

Kalmegh Extract (Standardized Andrographis paniculata): Composition represents a generic representative A. paniculata stem/leaf extract based on published phytochemical profiles, not HPLC analysis of a

Molecule	Percentage (%)	Role
Andrographolide	10%	primary diterpene lactone
Neoandrographolide	4.5%	—
14-Deoxy-11,12-didehydroandrographolide	2.5%	—
14-Deoxyandrographolide	3.5%	—
7-O-Methylwogonin	0.6%	flavonoid
Skullcapflavone I	0.6%	flavonoid

Black Pepper Extract

Molecule	Percentage (%)	Role
Piperine	95%	—

Recipes

Kalmegh Extract Capsule (no Piperine)

Ingredient	Type	Dose (mg)
Kalmegh Extract	extract	250 mg

Kalmegh Extract + Piperine Capsule

Ingredient	Type	Dose (mg)
Kalmegh Extract	extract	250 mg
Black Pepper Extract	extract	5.26 mg

Andrographolide Capsule (isolated compound)

Ingredient	Type	Dose (mg)
Andrographolide	pure compound	25 mg

Formulations

1. Kalmegh Extract Capsule (no Piperine)

Recipe: Kalmegh Extract Capsule (no Piperine)
Delivery Type: Capsule
Subtype: Powder
Extract Particle Radius Mean: 50 µm
Capsule Shell Lag Time: 10 min

2. Kalmegh Extract + Piperine Capsule

Recipe: Kalmegh Extract + Piperine Capsule
Delivery Type: Capsule
Subtype: Powder
Extract Particle Radius Mean: 50 µm
Piperine Particle Radius Mean: 40 µm
Capsule Shell Lag Time: 10 min

3. Andrographolide Capsule (isolated compound)

Recipe: Andrographolide Capsule (isolated compound)
Delivery Type: Capsule
Subtype: Powder
Particle Radius Mean: 50 µm
Capsule Shell Lag Time: 10 min

Population Settings

Population: Asian
Sample Size (n): 100
Age Range: 18–60

50%

Weight Range: 38.8–87.3 kg
BMI Range: 16.4–38.3 (mean 21.9)

Per-Compound Bioavailability (F%)

Bioavailability targets: the 3 primary diterpene lactones. All 6 kalmegh compounds + piperine (when present) are included in the formulation throughout all organs simulated for synergistic interaction modeling.

Scenario	Andrographolide	Neoandrographolide	14-Deoxy-DHA
Asian Population — Fed — Full Extract	29.22 ± 10.62%	16.59 ± 7.43%	9.57 ± 4.69%
Asian Population — Fasted — Full Extract	28.29 ± 10.37%	16.10 ± 7.22%	7.41 ± 3.66%
Asian Population — Fed — Extract + Piperine	30.57 ± 10.84%	18.35 ± 7.98%	9.82 ± 4.79%
Asian Population — Fed — Andrographolide Only	10.04 ± 5.30%	—	—

Key Comparisons

Synergistic Extract Enhancement (Andrographolide Alone vs Full Extract, Fed)

Condition	Andro F%	± SD	vs Alone
Andrographolide alone (25 mg)	10.04%	5.30%	Baseline
In Full Extract (no piperine)	29.22%	10.62%	2.9×
In Full Extract + Piperine	30.57%	10.84%	3.0×

Mechanism: The flavonoids 7-O-Methylwogonin and Skullcapflavone I in the extract inhibit CYP3A4 and CYP1A2, and reduce P-glycoprotein efflux, dramatically increasing andrographolide’s oral bioavailability. This explains why whole-herb Kalmegh extracts are traditionally more effective than isolated andrographolide.

Piperine Enhancement (Fed State, Full Extract)

Compound	No Piperine	+ Piperine	Enhancement
Andrographolide	29.22%	30.57%	1.05×
Neoandrographolide	16.59%	18.35%	1.11×
14-Deoxy-DHA	9.57%	9.82%	1.03×

Piperine (5 mg) provides additional CYP3A4 inhibition and P-gp efflux reduction beyond what the extract already achieves. The marginal gain is modest because the extract’s own flavonoids already provide substantial enzyme inhibition.

Fed vs Fasted (Full Extract, No Piperine)

Compound	Fed	Fasted	Food Effect
Andrographolide	29.22%	28.29%	1.03×
Neoandrographolide	16.59%	16.10%	1.03×
14-Deoxy-DHA	9.57%	7.41%	1.29×

Population Variability (Asian Population, n=100, Fed, Full Extract)

Compound	F% Mean	± SD	CV%	n
Andrographolide	29.22%	10.62%	36%	100
Neoandrographolide	16.59%	7.43%	45%	100
14-Deoxy-DHA	9.57%	4.69%	49%	100
Andro. (alone, no extract)	10.04%	5.30%	53%	100

Note: Andrographolide alone (no extract) shows higher inter-individual variability (CV 53%) than in the full extract (CV 36%), suggesting that the synergistic enhancement from co-extracted flavonoids not only boosts mean bioavailability but also reduces population variability — a desirable quality for consistent clinical response.