Simulaite Report

We simulated oral bioavailability (F) for seven bioactive compounds across Fenugreek (500 mg) and Shatavari (300 mg) extracts using the Simulaite PBPK engine. Two fed-state Asian virtual populations were modeled: a general adult cohort (n=100, 50% female, ages 18-60y) and the target demographic, Menopausal Women age 45–55 (n=100, 100% female, ages 45-55y). The six-run matrix isolates compound baselines, extract self-DDI, and cross-extract PK interactions.

Key Takeaways

• Menopausal Women show lower systemic exposure across the full combined formulation; the mean saponin F shift is -16.9% relative to general adults.
• Trigonelline stands out for Menopausal Women: high predicted bioavailability (42.1% F) plus reported picomolar phytoestrogen activity (Allred et al. (2009)).
• 4-Hydroxyisoleucine remains the most systemically available active: 92.9% F in general adults and 91.7% in Menopausal

Women.

• Saponin parent-compound exposure is low but non-zero: general combined-run F spans 0.70–0.91%; Menopausal Women spans 0.58–0.76%.
• Cross-extract DDI is still modest for saponins, but flavonoids respond: Quercetin rises 1.30× and Rutin rises 1.21× in the combined general-adult formulation versus Shatavari alone.

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.

Fenugreek Extract (500 mg)

Shatavari Extract (300 mg)

Protodioscin Alone

Delivery Type

Capsule

Subtype

Powder

Protodioscin Dose

20 mg

Particle Radius Mean

50.0 µm

Shatavarin-IV Alone

Delivery Type

Capsule

Subtype

Powder

Shatavarin IV Dose

21 mg

Particle Radius Mean

50.0 µm

Protodioscin + Shatavarin-IV Pair

Delivery Type

Capsule

Subtype

Powder

Protodioscin Dose

20 mg

Shatavarin IV Dose

21 mg

Particle Radius Mean

50.0 µm

Fenugreek Extract (Full)

Delivery Type

Capsule

Subtype

Powder

Fenugreek Extract Dose

500 mg

Particle Radius Mean

50.0 µm

Shatavari Extract (Full)

Delivery Type

Capsule

Subtype

Powder

Shatavari Extract Dose

300 mg

Particle Radius Mean

50.0 µm

Fenugreek + Shatavari Combined

Delivery Type

Capsule

Subtype

Powder

Fenugreek Extract Dose

500 mg

Shatavari Extract Dose

300 mg

Particle Radius Mean

50.0 µm

Each population ran the same six-scenario matrix to isolate single-compound baselines, pair DDI, extract self-DDI, and full cross-extract DDI.

Combined Formulation F% Plot

Full formulation bioavailability by compound. Bars compare the general adult reference population against Menopausal Women;

error bars show ±1 SD.

Per-Compound Bioavailability — General Population

Asian, 50% female, ages 18–60, fed state. Evaluable n range: 99–100.

Per-Compound Bioavailability — Menopausal Women

Asian, 100% female, fed state. Age range defined in Population Settings.

Population Delta — Combined Formulation

PK Parameter Table — Combined Formulation

AUC is oral AUC over the simulated 24 h horizon, calculated from individual plasma curves and converted to ng/mL·h using each compound molecular weight from the result JSON. Cmax is ng/mL; Tmax is hours.

Cross-Extract DDI Analysis — General Population

The n=100 results show minimal cross-extract PK enhancement for saponins. Quercetin and Rutin increase more clearly in the combined extract, consistent with UGT1A1 interaction and extract context, but this does not rescue parent saponin exposure.

Median plasma concentration-time profiles for the full combined extract formulation with P5–P95 uncertainty bands.

Protodioscin: Plasma Concentration-Time Curve

Trigonelline: Plasma Concentration-Time Curve

4-Hydroxyisoleucine: Plasma Concentration-Time Curve

Shatavarin IV: Plasma Concentration-Time Curve

Shatavarin I: Plasma Concentration-Time Curve

Quercetin: Plasma Concentration-Time Curve

Rutin: Plasma Concentration-Time Curve

Reference: Naveencharan, R. et al. "Validation of combination of protodioscin and shatavarin IV from medicinal extracts for alleviating menopausal symptoms by computational deep learning models." Talanta Open, 2025, 100552. doi:10.1016/ j.talo.2025.100552

Their study emphasizes pharmacodynamic modeling and static ADME flags for the two headline compounds, Protodioscin and Shatavarin IV. This report answers the complementary PK question: after the real extract-standardized oral capsule dose, what plasma exposure is achievable across a virtual target population?

Most Important New Findings

• Parent saponin exposure remains low in the combined formulation: Shatavarin IV is 0.70% F in general adults and 0.58% in Menopausal Women.
• The highest systemic exposure comes from 4-Hydroxyisoleucine and Trigonelline, which were not the main focus of the reference paper.
• Trigonelline may be especially relevant to menopausal symptom biology: Allred et al. (2009) identified it as a novel phytoestrogen with ER activity at picomolar concentrations via a non-classical mechanism.
• Cross-extract PK enhancement is modest for saponins, so any strong in-vivo benefit likely depends more on pharmacodynamic complementarity and/or metabolite biology than parent-compound bioavailability alone.

CYP and UGT enzyme contributions to total intrinsic clearance, plus P-glycoprotein efflux substrate status. Values are derived from our GNN suite predictions and integrated into the PBPK simulation. The GNN models predict substrate probability, intrinsic clearance per enzyme, and inhibition probability — all applied during simulation.

Substrate Profile — Enzymes & Transporters

Intrinsic clearance (CLint) fractions per compound, predicted by our GNN suite from molecular structure. Bold teal = dominant clearance enzyme.

Inhibition Profile — Enzymes & Transporters

Inhibition probabilities predicted by our GNN suite. Cross-compound DDI factors are computed from these values and applied during simulation.

Metabolic Insights

• UGT1A1 glucuronidation remains the dominant modeled pathway for saponins and flavonoids.
• 4-Hydroxyisoleucine is handled as an amino-acid-like molecule with effectively zero CYP/UGT clearance, supporting its high

F%.

• Saponins are modeled as P-gp substrates with very low permeability, explaining high variability and low parent exposure.
• Quercetin and Rutin inhibit UGT1A1 in the model; their co-formulation increases flavonoid exposure more than saponin exposure.